Compounds having selective cytochrome P450RAI-1 or selective cytochrome P450RAI-2 inhibitory activity and methods of obtaining the same

ABSTRACT

Compounds of formulas 1 through 17 provided in the specification specifically or selectively inhibit either the cytochrome P450RAI-1 enzyme or the cytochrome P450RAI-2 enzyme.

RELATED APPLICATION(S)

This application is a continuation of Ser. No. 11/014,460, filed on Dec.16, 2004, which claims the benefit of U.S. Provisional Application No.60/530,462, filed on Dec. 17, 2003. The entire teachings of the aboveapplication are incorporated herein by reference.

BACKGROUND OF THE INVENTION

The present invention is directed to compounds having selectivecytochrome P450RAI-1 or selective cytochrome P450RAI-2 inhibitoryactivity and to methods of obtaining these compounds.

Compounds that have retinoid-like activity are well known in the art,and are described in numerous United States and other patents and inscientific publications. It is generally known and accepted in the artthat retinoid-like activity is useful for treating animals of themammalian species, including humans, for curing or alleviating thesymptoms and conditions of numerous diseases and conditions. In otherwords, it is generally accepted in the art that pharmaceuticalcompositions having a retinoid-like compound or compounds as the activeingredient are useful as regulators of cell proliferation anddifferentiation, and particularly as agents for treating skin-relateddiseases, including, actinic keratoses, arsenic keratoses, inflammatoryand non-inflammatory acne, psoriasis, ichthyoses and otherkeratinization and hyperproliferative disorders of the skin, eczema,atopic dermatitis, Darriers disease, lichen planus, prevention andreversal of glucocorticoid damage (steroid atrophy), as a topicalanti-microbial, as skin anti-pigmentation agents and to treat andreverse the effects of age and photo damage to the skin. Retinoidcompounds are also useful for the prevention and treatment of cancerousand precancerous conditions, including, premalignant and malignanthyperproliferative diseases such as cancers of the breast, skin,prostate, cervix, uterus, colon, bladder, esophagus, stomach, lung,larynx, oral cavity, blood and lymphatic system, metaplasias,dysplasias, neoplasias, leukoplakias and papillomas of the mucousmembranes and in the treatment of Kaposi's sarcoma. In addition,retinoid compounds can be used as agents to treat diseases of the eye,including, without limitation, proliferative vitreoretinopathy (PVR),retinal detachment, dry eye and other corneopathies, as well as in thetreatment and prevention of various cardiovascular diseases, including,without limitation, diseases associated with lipid metabolism such asdyslipidemias, prevention of post-angioplasty restenosis and as an agentto increase the level of circulating tissue plasminogen activator (TPA).Other uses for retinoid compounds include the prevention and treatmentof conditions and diseases associated with human papilloma virus (HPV),including warts and genital warts, various inflammatory diseases such aspulmonary fibrosis, ileitis, colitis and Krohn's disease,neurodegenerative diseases such as Alzheimer's disease, Parkinson'sdisease and stroke, improper pituitary function, including insufficientproduction of growth hormone, modulation of apoptosis, including boththe induction of apoptosis and inhibition of T-Cell activated apoptosis,restoration of hair growth, including combination therapies with thepresent compounds and other agents such as Minoxidil®, diseasesassociated with the immune system, including use of the presentcompounds as immunosuppressants and immunostimulants, modulation oforgan transplant rejection and facilitation of wound healing, includingmodulation of chelosis. Retinoid compounds have relatively recently beenalso discovered to be useful for treating type II non-insulin dependentdiabetes mellitus (NIDDM).

Several compounds having retinoid-like activity are actually marketedunder appropriate regulatory approvals in the United States of Americaand elsewhere as medicaments for the treatment of several diseasesresponsive to treatment with retinoids. Retinoic acid (RA) itself is anatural product, biosynthesized and present in a multitude of human andmammalian tissues and is known to play an important role in theregulation of gene expression, tissue differentiation and otherimportant biological processes in mammals including humans. Relativelyrecently it has been discovered that a catabolic pathway in mammals,including humans, of natural retinoic acid includes a step ofhydroxylation of RA catalyzed by the enzyme Cytochrome P450RAI (retinoicacid inducible). In fact, in the present state of the art it is knownthat at least three sub-species of cytochrome P450RAI enzymes exist, andthese are termed P450RAI1, P450RAI2 and P450RAI3. White et al.Identification of the human cytochrome P450, P450RAI-2, which ispredominantly expressed in the adult cerebellum and is responsible forall trans retinoic acid metabolism, Proc. Natl. Acad. Sci. USA Volume 97No. 12 pp 6403 6408 (Jun. 6, 2000).

Several inhibitors of cytochrome P450RAI have been synthesized ordiscovered in the prior art, including the well known ketoconazole,liarozole and R116010 compounds. The chemical structures of these priorart compounds are provided below. U.S. Pat. No. 6,313,107 describes anumber of compounds having cytochrome P450RAI inhibitory activity.

It has also been noted in the prior art, that administration to mammals,including humans, of certain inhibitors of CP-450RAI results insignificant increase in endogeneous RA levels, and further thattreatment with CP450RAI inhibitors, for example with liarozole, givesrise to effects similar to treatment by retinoids, for exampleamelioration of psoriasis.

The following publications describe or relate to the above-summarizedrole of CP450RAI in the natural catabolism of RA, to inhibitors ofCP-450RAI and to in vitro and in vivo experiments which demonstrate thatinhibition of CP450RAI activity results in increased endogeneous RAlevels and potential therapeutic benefits:

-   Kuijpers, et al., “The effects of oral liarozole on epidermal    proliferation and differentiation in severe plaque psoriasis are    comparable with those of acitretin”, British Journal of    Dermatology, (1998) 139: pp 380-389.-   Kang, et al., “Liarozole Inhibits Human Epidermal Retinoid Acid    4-Hydroxylase Activity and Differentially Augments Human Skin    Responses to Retinoic Acid and Retinol In Vivo”, The Journal of    Investigative Dermatology, (August 1996) Vol. 107, No. 2: pp    183-187.-   Van Wauwe, et al., “Liarozole, an Inhibitor of Retinoic Acid    Metabolism, Exerts Retinoid-Mimetic Effects in Vivo”, The Journal of    Pharmacology and Experimental Therapeutics, (1992) Vol. 261, No 2:    pp 773-779.-   De Porre, et al., “Second Generation Retinoic Acid Metabolism    Blocking Agent (Ramba) R116010: Dose Finding in Healthy Male    Volunteers”, University of Leuven, Belgium, pp 30.-   Wauwe, et al., “Ketoconazole Inhibits the in Vitro and in Vivo    Metabolism of All-Trans-Retinoic Acid”, The Journal of Pharmacology    and Experimental Therapeutics, (1988) Vol. 245, No. 2: pp 718-722.-   White, et al., “cDNA Cloning of Human Retinoic Acid-metabolizing    Enzyme (hP450RAI) Identifies a Novel Family of Cytochromes P450, The    Journal of Biological Chemistry, (1997) Vol. 272, No. 30, Issue of    July 25 pp 18538-18541.-   Hanzlik, et al., “Cyclopropylamines as Suicide Substrates for    Cytochromes P450RAI”, Journal of Medicinal Chemistry (1979), Vol.    22, No. 7, pp 759-761.-   Oriiz de Montellano, “Topics in Biology—The Inactivation of    Cytochrome P450RAI”, Annual Reports in Medicinal Chemistry, (1984),    Chapter 20, pp 201-210.-   Hanzlik, et al. “Suicidal Inactivation of Cytochrome P450RAI by    Cyclopropylamines-Evidence for Cation-Radical Intermediates”, J. Am.    Chem. Soc., (1982), Vol. 104, No. 107, pp. 2048-2052. White et al.    Proc. Natl. Acad. Sci. USA supra.

It is now general knowledge in the art that two main types of retinoidreceptors exist in mammals (and other organisms). The two main types orfamilies of receptors are respectively designated the RARs and RXRs.Within each type there are subtypes; in the RAR family the subtypes aredesignated RAR_(α), RAR_(β) and RAR_(γ), in RXR the subtypes are:RXR_(α), RXR_(β) and RXR_(γ). It has also been established in the artthat the distribution of the two main retinoid receptor types, and ofthe several sub-types is not uniform in the various tissues and organsof mammalian organisms. Moreover, it is generally accepted in the artthat many unwanted side effects of retinoids are mediated by one or moreof the RAR receptor subtypes. Accordingly, among compounds havingagonist-like activity at retinoid receptors, specificity or selectivityfor one of the main types or families, and even specificity orselectivity for one or more subtypes within a family of receptors, isconsidered a desirable pharmacological property.

Similar to the desirability of providing compounds that are selective orspecific to one or more retinoid receptor subtypes, it is also desirableto provide compounds that specifically or selectively inhibit either thecytochrome P450RAI-1 enzyme or the cytochrome P450RAI-2 enzyme. Thepresent invention provides such compounds and methods in the form ofsynthetic guidelines how to obtain them.

SUMMARY OF THE INVENTION

The present invention relates to compounds of Formula I

wherein

A is a phenyl or naphthyl group, or heteroaryl selected from a groupconsisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl,pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyland heteroaryl groups being optionally substituted with one or two R₂groups;

X is O, S or NR where R is H, alkyl of 1 to 6 carbons or benzyl;

Y is H, alkyl of 1 to 10 carbons, benzyl, C₁₋₆ alkyl or halogensubstituted benzyl, fluoro-substituted alkyl of 1 to 10 carbons,cycloalkyl of 3 to 6 carbons, C₁₋₆ alkyl substituted cycloalkyl of 3 to6 carbons, alkenyl of 2 to 6 carbons and having 1 or 2 double bonds,alkynyl of 2 to 6 carbons, alkenyl-alkynyl of 4 to 6 carbons,alkynyl-alkenyl of 4 to 6 carbons, Cl, Br, or I or alkoxy of 1 to 6carbons;

Z is —C≡C—,

-   -   —(CR₁═CR₁)_(n′) where n′ is an integer having the value 1-5,    -   —CO—NR₁—,    -   NR₁—CO—;    -   —CO—O—,    -   —O—CO—,    -   —CS—NR₁—,    -   NR₁—CS—,    -   —CO—S—,    -   —S—CO—,    -   —N═N—;

—NR₁—CO—NR₁—;

R₁ is independently H or alkyl of 1 to 6 carbons;

p is an integer having the values of 0 to 4;

R₂ is independently H, alkyl of 1 to 6 carbons, F, Cl, Br, I, CF₃,fluoro substituted alkyl of 1 to 6 carbons, alkoxy of 1 to 6 carbons, oralkylthio of 1 to 6 carbons;

R₃ is independently alkyl of 1 to 6 carbons, F, Cl, Br, I, fluorosubstituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons,alkylthio of 1 to 6 carbons or benzyl;

m is an integer having the values 0 to 2;

R₄ is independently H, alkyl of 1 to 6 carbons, or F, fluorosubstitutedalkyl of 1 to 6 carbons, or halogen;

o is an integer having the values of 0 to 2;

W is —C(R₅)₂— or —CR₅═CR₅—;

R₅ is independently H, halogen, or alkyl of 1 to 3 carbons with theproviso that when W is —C(R₅)₂— then at least one R₅ is alkyl of 1 to 3carbons, and

R₈ is H, alkyl of 1 to 6 carbons, —CH₂O(C₁₋₆-alkyl), CH₂OCO(C₁₋₆-alkyl)or a cation of a pharmaceutically acceptable base.

The present invention also relates to compounds of Formula 2

wherein the dashed line represents a bond or absence of a bond;

A is a phenyl or naphthyl group, or heteroaryl selected from a groupconsisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl,pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyland heteroaryl groups being optionally substituted with one or two R₂groups;

X is alkyl of 1 to 6 carbons, alkenyl of 2 to 6 carbons and having 1 or2 double bonds, alkynyl of 2 to 6 carbons, alkenyl-alkynyl of 4 to 6carbons, alkynyl-alkenyl of 4 to 6 carbons, Cl, Br, or I, OR, SR, NRR₇,—CO—OR where R is H, alkyl of 1 to 6 carbons or benzyl;

Y is H, alkyl of 1 to 10 carbons, benzyl, C₁₋₆ alkyl or halogensubstituted benzyl, fluoro-substituted alkyl of 1 to 10 carbons,cycloalkyl of 3 to 6 carbons, C₁₋₆ alkyl substituted cycloalkyl of 3 to6 carbons, alkenyl of 2 to 6 carbons and having 1 or 2 double bonds,alkynyl of 2 to 6 carbons, alkenyl-alkynyl of 4 to 6 carbons,alkynyl-alkenyl of 4 to 6 carbons, Cl, Br, I, COOR₈ or alkoxy of 1 to 6carbons;

Z is —C≡C—,

-   -   —(CR₁═CR₁)_(n′) where n′ is an integer having the value 1-5,    -   —CO—NR₁—,    -   NR₁—CO—;    -   —CO—O—,    -   —O—CO—,    -   —CS—NR₁—,    -   NR₁—CS—,    -   —CO—S—,    -   —S—CO—,    -   —N═N—;    -   —NR₁—CO—NR₁—;

R₁ is independently H or alkyl of 1 to 6 carbons;

R₂ is independently H, alkyl of 1 to 6 carbons, F, Cl, Br, I, CF₃,fluoro substituted alkyl of 1 to 6 carbons, alkoxy of 1 to 6 carbons, oralkylthio of 1 to 6 carbons;

R₃ is independently alkyl of 1 to 6 carbons, F, Cl, Br, I, fluorosubstituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons,alkylthio of 1 to 6 carbons or benzyl;

m is an integer having the values 0 to 2;

R₄ is independently H, alkyl of 1 to 6 carbons, or fluorosubstitutedalkyl of 1 to 6 carbons, or halogen;

o is an integer having the values of 0 to 4;

W is —C(R₅)₂— or —CR₅═CR₅—;

R₅ is independently H, halogen, or alkyl of 1 to 3 carbons with theproviso that when W is —C(R₅)₂— then at least one R₅ is alkyl of 1 to 3carbons;

R₇ is H, lower alkyl, cycloalkyl of 3 to 6 carbons, lower alkylsubstituted cycloalkyl of 3 to 6 carbons, and

R₈ is H, alkyl of 1 to 6 carbons, —CH₂O(C₁₋₆-alkyl), CH₂OCO(C₁₋₆-alkyl)or a cation of a pharmaceutically acceptable base.

The present invention also relates to compounds of Formula 3

wherein A is a phenyl or naphthyl group, or heteroaryl selected from agroup consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl,pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyland heteroaryl groups being optionally substituted with one or two R₂groups;

X is O, S or NR where R is H, alkyl of 1 to 6 carbons,C₁₋₆-trialkylsilyl or benzyl;

Y is H, alkyl of 1 to 10 carbons, benzyl, C₁₋₆ alkyl or halogensubstituted benzyl, fluoro-substituted alkyl of 1 to 10 carbons,cycloalkyl of 3 to 6 carbons, C₁₋₆ alkyl substituted cycloalkyl of 3 to6 carbons, alkenyl of 2 to 6 carbons and having 1 or 2 double bonds,alkynyl of 2 to 6 carbons, alkenyl-alkynyl of 4 to 6 carbons,alkynyl-alkenyl of 4 to 6 carbons, Cl, Br, or I;

Z is —C≡C—,

-   -   —(CR₁═CR₁)_(n′) where n′ is an integer having the value 1-5,    -   —CO—NR₁—,    -   NR₁—CO—;    -   —CO—O—,    -   —O—CO—,    -   —CS—NR₁—,    -   NR₁—CS—,    -   —CO—S—,    -   —S—CO—,    -   —N═N—;    -   —NR₁—CO—NR₁—;

R₁ is independently H or alkyl of 1 to 6 carbons;

R₂ is independently H, alkyl of 1 to 6 carbons, F, Cl, Br, I, CF₃,fluoro substituted alkyl of 1 to 6 carbons, alkoxy of 1 to 6 carbons, oralkylthio of 1 to 6 carbons;

R₃ is independently alkyl of 1 to 6 carbons, F, Cl, Br, I, fluorosubstituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons,alkylthio of 1 to 6 carbons or benzyl;

m is an integer having the values 0 to 3;

W is —C(R₅)₂— or —CR₅═CR₅—;

R₅ is independently H, halogen, or alkyl of 1 to 3 carbons with theproviso that when W is —C(R₅)₂— then at least one R₅ is alkyl of 1 to 3carbons;

R₇ is H, alkyl of 1 to 6 carbons, cycloalkyl of 3 to 6 carbons or C₁₋₆alkyl substituted cycloalkyl of 1 to 6 carbons, and

R₈ is H, alkyl of 1 to 6 carbons, —CH₂O(C₁₋₆-alkyl), CH₂OCO(C₁₋₆-alkyl)or a cation of a pharmaceutically acceptable base.

The present invention also relates to compounds of Formula 4

wherein A is a phenyl or naphthyl group, or heteroaryl selected from agroup consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl,pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyland heteroaryl groups being optionally substituted with one or two R₂groups;

X is OR₇, SR₇ or NRR₇ where R is H, alkyl of 1 to 6 carbons or benzyl;

Y is H, alkyl of 1 to 10 carbons, benzyl, C₁₋₆ alkyl or halogensubstituted benzyl, fluoro-substituted alkyl of 1 to 10 carbons,cycloalkyl of 3 to 6 carbons, C₁₋₆ alkyl substituted cycloalkyl of 3 to6 carbons, alkenyl of 2 to 6 carbons and having 1 or 2 double bonds,alkynyl of 2 to 6 carbons, alkenyl-alkynyl of 4 to 6 carbons,alkynyl-alkenyl of 4 to 6 carbons, Cl, Br, I, or —COOR₁;

Z is —C≡C—,

-   -   —(CR₁═CR₁)_(n′) where n′ is an integer having the value 1-5,    -   —CO—NR₁—,    -   NR₁—CO—;    -   —CO—O—,    -   —O—CO—,    -   —CS—NR₁—,    -   NR₁—CS—,    -   —CO—S—,    -   —S—CO—,    -   —N═N—;    -   —NR₁—CO—NR₁—;

R₁ is independently H or alkyl of 1 to 6 carbons;

R₂ is independently H, alkyl of 1 to 6 carbons, F, Cl, Br, I, CF₃,fluoro substituted alkyl of 1 to 6 carbons, alkoxy of 1 to 6 carbons, oralkylthio of 1 to 6 carbons;

R₃ is independently alkyl of 1 to 6 carbons, F, Cl, Br, I, fluorosubstituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons,alkylthio of 1 to 6 carbons or benzyl;

m is an integer having the values 0 to 3;

W is —C(R₅)₂— or —CR₅═CR₅—;

R₅ is independently H, halogen, or alkyl of 1 to 3 carbons with theproviso that when W is —C(R₅)₂— then at least one R₅ is alkyl of 1 to 3carbons;

R₇ is H, alkyl of 1 to 6 carbons, cycloalkyl of 3 to 6 carbons or C₁₋₆alkyl substituted cycloalkyl of 1 to 6 carbons, and

R₈ is H, alkyl of 1 to 6 carbons, —CH₂O(C₁₋₆-alkyl), CH₂OCO(C₁₋₆-alkyl)or a cation of a pharmaceutically acceptable base.

The present invention also relates to compounds of Formula 5

wherein A is a phenyl or naphthyl group, or heteroaryl selected from agroup consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl,pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyland heteroaryl groups being optionally substituted with one or two R₂groups;

Y is H, alkyl of 1 to 10 carbons, benzyl, C₁₋₆ alkyl or halogensubstituted benzyl, fluoro-substituted alkyl of 1 to 10 carbons,cycloalkyl of 3 to 6 carbons, C₁₋₆ alkyl substituted cycloalkyl of 3 to6 carbons, alkenyl of 2 to 6 carbons and having 1 or 2 double bonds,alkynyl of 2 to 6 carbons, alkenyl-alkynyl of 4 to 6 carbons,alkynyl-alkenyl of 4 to 6 carbons, Cl, Br, I, or —COOR₁;

Z is —C≡C—,

-   -   —(CR₁═CR₁)_(n′) where n′ is an integer having the value 1-5,    -   —CO—NR₁—,    -   NR₁—CO—;    -   —CO—O—,    -   —O—CO—,    -   —CS—NR₁—,    -   NR₁—CS—,    -   —CO—S—,    -   —S—CO—,    -   —N═N—;    -   —NR₁—CO—NR₁—;

R₁ is independently H or alkyl of 1 to 6 carbons;

R₂ is independently H, alkyl of 1 to 6 carbons, F, Cl, Br, I, CF₃,fluoro substituted alkyl of 1 to 6 carbons, alkoxy of 1 to 6 carbons, oralkylthio of 1 to 6 carbons;

R₃ is independently alkyl of 1 to 6 carbons, F, Cl, Br, I, fluorosubstituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons,alkylthio of 1 to 6 carbons or benzyl;

m is an integer having the values 0 to 3;

n is an integer having the values of 0 or 1;

p is an integer having the values of 0 or 1;

W is —C(R₅)₂— or —CR₅═CR₅—;

R₅ is independently H, halogen, or alkyl of 1 to 3 carbons with theproviso that when W is —C(R₅)₂— then at least one R₅ is alkyl of 1 to 3carbons, and

R₈ independently is H, alkyl of 1 to 6 carbons, —CH₂O(C₁₋₆-alkyl),CH₂OCO(C₁₋₆-alkyl) or a cation of a pharmaceutically acceptable base.

The present invention also relates to compounds of Formula 6

wherein A is a phenyl or naphthyl group, or heteroaryl selected from agroup consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl,pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyland heteroaryl groups being optionally substituted with one or two R₂groups;

X is O, S, NR or CO where R is H or alkyl of 1 to 6 carbons;

Y is H, alkyl of 1 to 10 carbons, benzyl, C₁₋₆ alkyl or halogensubstituted benzyl, fluoro-substituted alkyl of 1 to 10 carbons,cycloalkyl of 3 to 6 carbons, C₁₋₆ alkyl substituted cycloalkyl of 3 to6 carbons, alkenyl of 2 to 6 carbons and having 1 or 2 double bonds,alkynyl of 2 to 6 carbons, alkenyl-alkynyl of 4 to 6 carbons,alkynyl-alkenyl of 4 to 6 carbons, Cl, Br, I, OR₇, CH₂—NRR₇ or —COOR₁;

Z is —C≡C—,

-   -   —(CR₁═CR₁)_(n′) where n′ is an integer having the value 1-5,    -   —CO—NR₁—,    -   NR₁—CO—;    -   —CO—O—,    -   —O—CO—,    -   —CS—NR₁—,    -   NR₁—CS—,    -   —CO—S—,    -   —S—CO—,    -   —N═N—;    -   —NR₁—CO—NR₁—;

R₁ is independently H or alkyl of 1 to 6 carbons;

R₂ is independently H, alkyl of 1 to 6 carbons, F, Cl, Br, I, CF₃,fluoro substituted alkyl of 1 to 6 carbons, alkoxy of 1 to 6 carbons, oralkylthio of 1 to 6 carbons;

R₃ is independently alkyl of 1 to 6 carbons, F, Cl, Br, I, fluorosubstituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons,alkylthio of 1 to 6 carbons or benzyl;

m is an integer having the values 0 to 3;

R₄ is independently H, alkyl of 1 to 6 carbons, or F; fluorosubstitutedalkyl of 1 to 6 carbons, or halogen;

o is an integer having the values of 0 to 4;

W is —C(R₅)₂— or —CR₅═CR₅—;

R₅ is independently H, halogen, or alkyl of 1 to 3 carbons with theproviso that when W is —C(R₅)₂— then at least one R₅ is alkyl of 1 to 3carbons, and

R₇ is H, alkyl of 1 to 6 carbons, cycloalkyl of 3 to 6 carbons or C₁₋₆alkyl substituted cycloalkyl of 1 to 6 carbons, and

R₈ is H, alkyl of 1 to 6 carbons, —CH₂O(C₁₋₆-alkyl), CH₂OCO(C₁₋₆-alkyl)or a cation of a pharmaceutically acceptable base.

The present invention also relates to compounds of Formula 7

wherein A is a phenyl or naphthyl group, or heteroaryl selected from agroup consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl,pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyland heteroaryl groups being optionally substituted with one or two R₂groups;

Y is alkenyl-alkynyl of 4 to 6 carbons, alkynyl-alkenyl of 4 to 6carbons, OR₇, CH₂—NRR₇ or —COOR₁;

Z is —C≡C—,

-   -   —CO—O—,    -   —NR₁—CO—NR₁—;

R is independently H or alkyl of 1 to 6 carbons;

R₁ is independently H or alkyl of 1 to 6 carbons;

R₂ is independently H, alkyl of 1 to 6 carbons, F, Cl, Br, I, CF₃,fluoro substituted alkyl of 1 to 6 carbons, alkoxy of 1 to 6 carbons, oralkylthio of 1 to 6 carbons;

R₃ is independently alkyl of 1 to 6 carbons, F, Cl, Br, I, fluorosubstituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons,alkylthio of 1 to 6 carbons or benzyl;

m is an integer having the values 0 to 3;

R₄ is independently H, alkyl of 1 to 6 carbons, or F; fluorosubstitutedalkyl of 1 to 6 carbons, or halogen;

o is an integer having the values of 0 to 4;

R₇ is H, alkyl of 1 to 6 carbons, cycloalkyl of 3 to 6 carbons or C₁₋₆alkyl substituted cycloalkyl of 1 to 6 carbons, and

R₈ is H, alkyl of 1 to 6 carbons, —CH₂O(C₁₋₆-alkyl), CH₂OCO(C₁₋₆-alkyl)or a cation of a pharmaceutically acceptable base.

The present invention also relates to compounds of Formula 8

wherein A is a phenyl or naphthyl group, or heteroaryl selected from agroup consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl,pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyland heteroaryl groups being optionally substituted with one or two R₂groups;

Y is alkenyl of 2 to 6 carbons, alkynyl of 2 to 6 carbons,alkenyl-alkynyl of 4 to 6 carbons, alkynyl-alkenyl of 4 to 6 carbons;

Z is —C≡C—,

-   -   —CO—O—,    -   —NR₁—CO—NR₁—;

R₁ is independently H or alkyl of 1 to 6 carbons;

R₂ is independently H, alkyl of 1 to 6 carbons, F, Cl, Br, I, CF₃,fluoro substituted alkyl of 1 to 6 carbons, alkoxy of 1 to 6 carbons, oralkylthio of 1 to 6 carbons;

R₃ is independently alkyl of 1 to 6 carbons, F, Cl, Br, I, fluorosubstituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons,alkylthio of 1 to 6 carbons or benzyl;

m is an integer having the values 0 to 3;

R₇ is H, alkyl of 1 to 6 carbons, cycloalkyl of 3 to 6 carbons or C₁₋₆alkyl substituted cycloalkyl of 1 to 6 carbons, and

R₈ is H, alkyl of 1 to 6 carbons, —CH₂O(C₁₋₆-alkyl), CH₂OCO(C₁₋₆-alkyl)or a cation of a pharmaceutically acceptable base.

The present invention also relates to compounds of Formula 9

wherein A is a phenyl or naphthyl group, or heteroaryl selected from agroup consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl,pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyland heteroaryl groups being optionally substituted with one or two R₂groups;

Z is —C≡C—,

-   -   —CO—O—,    -   —NR₁—CO—NR₁—;

R is H or alkyl of 1 to 6 carbons;

R₁ is independently H or alkyl of 1 to 6 carbons;

R₂ is independently H, alkyl of 1 to 6 carbons, F, Cl, Br, I, CF₃,fluoro substituted alkyl of 1 to 6 carbons, alkoxy of 1 to 6 carbons, oralkylthio of 1 to 6 carbons;

R₃ is independently alkyl of 1 to 6 carbons, F, Cl, Br, I, fluorosubstituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons,alkylthio of 1 to 6 carbons or benzyl;

m is an integer having the values 0 to 3;

R₇ is H, alkyl of 1 to 6 carbons, cycloalkyl of 3 to 6 carbons or C₁₋₆alkyl substituted cycloalkyl of 1 to 6 carbons, and

R₈ independently is H, alkyl of 1 to 6 carbons, —CH₂O(C₁₋₆-alkyl),CH₂OCO(C₁₋₆-alkyl) or a cation of a pharmaceutically acceptable base.

The present invention also relates to compounds of Formula 10

wherein the dashed line represents a bond or absence of a bond;

A is a phenyl or naphthyl group, or heteroaryl selected from a groupconsisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl,pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyland heteroaryl groups being optionally substituted with one or two R₂groups;

X is NRR₇, or COOR₈;

Y is H, alkenyl of 2 to 6 carbons, alkenyl-alkynyl of 4 to 6 carbons,alkynyl-alkenyl of 4 to 6 carbons, OR₇ or —COOR₁;

Z is —C≡C—,

-   -   —CO—O—,    -   —NR₁—CO—NR₁—;

R is independently H or alkyl of 1 to 6 carbons;

R₁ is independently H or alkyl of 1 to 6 carbons;

R₂ is independently H, alkyl of 1 to 6 carbons, F, Cl, Br, I, CF₃,fluoro substituted alkyl of 1 to 6 carbons, alkoxy of 1 to 6 carbons, oralkylthio of 1 to 6 carbons;

R₃ is independently alkyl of 1 to 6 carbons, F, Cl, Br, I, fluorosubstituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons,alkylthio of 1 to 6 carbons or benzyl;

m is an integer having the values 0 to 3;

R₄ is independently H, alkyl of 1 to 6 carbons, or F; fluorosubstitutedalkyl of 1 to 6 carbons, or halogen;

o is an integer having the values of 0 to 4;

R₇ is H, alkyl of 1 to 6 carbons, cycloalkyl of 3 to 6 carbons or C₁₋₆alkyl substituted cycloalkyl of 1 to 6 carbons, and

R₈ independently is H, alkyl of 1 to 6 carbons, —CH₂O(C₁₋₆-alkyl),CH₂OCO(C₁₋₆-alkyl) or a cation of a pharmaceutically acceptable base.

The present invention also relates to compounds of Formula 11

wherein A is a phenyl or naphthyl group, or heteroaryl selected from agroup consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl,pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyland heteroaryl groups being optionally substituted with one or two R₂groups;

Y is, alkenyl of 2 to 6 carbons, alkenyl-alkynyl of 4 to 6 carbons, oralkynyl-alkenyl of 4 to 6 carbons;

Z is —C≡C—,

-   -   —CO—O—,    -   —NR₁—CO—NR₁—;

R₁ is independently H or alkyl of 1 to 6 carbons;

R₂ is independently H, alkyl of 1 to 6 carbons, F, Cl, Br, I, CF₃,fluoro substituted alkyl of 1 to 6 carbons, alkoxy of 1 to 6 carbons, oralkylthio of 1 to 6 carbons;

R₃ is independently alkyl of 1 to 6 carbons, F, Cl, Br, I, fluorosubstituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons,alkylthio of 1 to 6 carbons or benzyl;

m is an integer having the values 0 to 3;

R₄ is independently H, alkyl of 1 to 6 carbons, or F; fluorosubstitutedalkyl of 1 to 6 carbons, or halogen;

o is an integer having the values of 0 to 4, and

R₈ is H, alkyl of 1 to 6 carbons, —CH₂O(C₁₋₆-alkyl), CH₂OCO(C₁₋₆-alkyl)or a cation of a pharmaceutically acceptable base.

The present invention also relates to compounds of Formula 12

wherein A is a phenyl or naphthyl group, or heteroaryl selected from agroup consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl,pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyland heteroaryl groups being optionally substituted with one or two R₂groups;

Z is —C≡C—,

-   -   —CO—O—,    -   —NR₁—CO—NR₁—;

R₁ is independently H or alkyl of 1 to 6 carbons;

R₂ is independently H, alkyl of 1 to 6 carbons, F, Cl, Br, I, CF₃,fluoro substituted alkyl of 1 to 6 carbons, alkoxy of 1 to 6 carbons, oralkylthio of 1 to 6 carbons;

R₃ is independently alkyl of 1 to 6 carbons, F, Cl, Br, I, fluorosubstituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons,alkylthio of 1 to 6 carbons or benzyl;

m is an integer having the values 0 to 3, and

R₈ independently is H, is alkyl of 1 to 6 carbons, —CH₂O(C₁₋₆-alkyl),CH₂OCO(C₁₋₆-alkyl) or a cation of a pharmaceutically acceptable base.

The present invention also relates to compounds of Formula 13

wherein A is a phenyl or naphthyl group, or heteroaryl selected from agroup consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl,pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyland heteroaryl groups being optionally substituted with one or two R₂groups;

Z is —C≡C—,

-   -   —CO—O—,    -   —NR₁—CO—NR₁—;

R₁ is independently H or alkyl of 1 to 6 carbons;

R₂ is independently H, alkyl of 1 to 6 carbons, F, Cl, Br, I, CF₃,fluoro substituted alkyl of 1 to 6 carbons, alkoxy of 1 to 6 carbons, oralkylthio of 1 to 6 carbons;

R₃ is independently alkyl of 1 to 6 carbons, F, Cl, Br, I, fluorosubstituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons,alkylthio of 1 to 6 carbons or benzyl;

m is an integer having the values 0 to 3, and

R₈ independently is H, alkyl of 1 to 6 carbons, —CH₂O(C₁₋₆-alkyl),CH₂OCO(C₁₋₆-alkyl) or a cation of a pharmaceutically acceptable base.

The present invention also relates to compounds of Formula 14

wherein A is a phenyl or naphthyl group, or heteroaryl selected from agroup consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl,pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyland heteroaryl groups being optionally substituted with one or two R₂groups;

Y is H, alkyl of 1 to 10 carbons, benzyl, C₁₋₆ alkyl or halogensubstituted benzyl, fluoro-substituted alkyl of 1 to 10 carbons,cycloalkyl of 3 to 6 carbons, C₁₋₆ alkyl substituted cycloalkyl of 3 to6 carbons, alkenyl of 2 to 6 carbons and having 1 or 2 double bonds,alkynyl of 2 to 6 carbons, alkenyl-alkynyl of 4 to 6 carbons,alkynyl-alkenyl of 4 to 6 carbons, Cl, Br, I, OR₇, CH₂—NRR₇ or —COOR₁;

R is independently H or alkyl of 1 to 6 carbons;

R₁ is independently H or alkyl of 1 to 6 carbons;

R₂ is independently H, alkyl of 1 to 6 carbons, F, Cl, Br, I, CF₃,fluoro substituted alkyl of 1 to 6 carbons, alkoxy of 1 to 6 carbons, oralkylthio of 1 to 6 carbons;

R₃ is independently alkyl of 1 to 6 carbons, F, Cl, Br, I, fluorosubstituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons,alkylthio of 1 to 6 carbons or benzyl;

m is an integer having the values 0 to 3;

R₄ is independently H, alkyl of 1 to 6 carbons, or F; fluorosubstitutedalkyl of 1 to 6 carbons, or halogen;

o is an integer having the values of 0 to 4;

R₇ is H, alkyl of 1 to 6 carbons, cycloalkyl of 3 to 6 carbons or C₁₋₆alkyl substituted cycloalkyl of 1 to 6 carbons, and

R₈ is 1-1, alkyl of 1 to 6 carbons, —CH₂O(C₁₋₆-alkyl),CH₂OCO(C₁₋₆-alkyl) or a cation of a pharmaceutically acceptable base.

The present invention also relates to compounds of Formula 15

wherein A is a phenyl or naphthyl group, or heteroaryl selected from agroup consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl,pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyland heteroaryl groups being optionally substituted with one or two R₂groups;

X is O or S;

Y is H, alkyl of 1 to 10 carbons, benzyl, C₁₋₆ alkyl or halogensubstituted benzyl, fluoro-substituted alkyl of 1 to 10 carbons,cycloalkyl of 3 to 6 carbons, C₁₋₆ alkyl substituted cycloalkyl of 3 to6 carbons, alkenyl of 2 to 6 carbons and having 1 or 2 double bonds,alkynyl of 2 to 6 carbons, alkenyl-alkynyl of 4 to 6 carbons,alkynyl-alkenyl of 4 to 6 carbons, Cl, Br, I, OR₇, CH₂—NRR₇ or —COOR₁;

R₁ is independently H or alkyl of 1 to 6 carbons;

p is an integer having the values of 0 to 4;

R₂ is independently H, alkyl of 1 to 6 carbons, F, Cl, Br, I, CF₃,fluoro substituted alkyl of 1 to 6 carbons, alkoxy of 1 to 6 carbons, oralkylthio of 1 to 6 carbons;

R₃ is independently alkyl of 1 to 6 carbons, F, Cl, Br, I, fluorosubstituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons,alkylthio of 1 to 6 carbons or benzyl;

m is an integer having the values 0 to 3;

R₄ is independently H, alkyl of 1 to 6 carbons, or F; fluorosubstitutedalkyl of 1 to 6 carbons, or halogen;

o is an integer having the values of 0 to 4;

R₇ is H, alkyl of 1 to 6 carbons, cycloalkyl of 3 to 6 carbons or C₁₋₆alkyl substituted cycloalkyl of 1 to 6 carbons, and

R₈ is H, alkyl of 1 to 6 carbons, —CH₂O(C₁₋₆-alkyl), CH₂OCO(C₁₋₆-alkyl)or a cation of a pharmaceutically acceptable base.

The present invention also relates to compounds of Formula 16

wherein A is a phenyl or naphthyl group, or heteroaryl selected from agroup consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl,pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyland heteroaryl groups being optionally substituted with one or two R₂groups;

R₂ is independently H, alkyl of 1 to 6 carbons, F, Cl, Br, I, CF₃,fluoro substituted alkyl of 1 to 6 carbons, alkoxy of 1 to 6 carbons, oralkylthio of 1 to 6 carbons;

R₃ is independently alkyl of 1 to 6 carbons, F, Cl, Br, I, fluorosubstituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons,alkylthio of 1 to 6 carbons or benzyl;

m is an integer having the values 0 to 3, and

R₈ independently is 1-1, alkyl of 1 to 6 carbons, —CH₂O(C₁₋₆-alkyl),CH₂OCO(C₁₋₆-alkyl) or a cation of a pharmaceutically acceptable base.

The present invention also relates to compounds of Formula 17

wherein A is a phenyl or naphthyl group, or heteroaryl selected from agroup consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl,pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyland heteroaryl groups being optionally substituted with one or two R₂groups;

X is O or S;

Y is H, alkyl of 1 to 10 carbons, benzyl, C₁₋₆ alkyl or halogensubstituted benzyl, fluoro-substituted alkyl of 1 to 10 carbons,cycloalkyl of 3 to 6 carbons, C₁₋₆ alkyl substituted cycloalkyl of 3 to6 carbons, alkenyl of 2 to 6 carbons and having 1 or 2 double bonds,alkynyl of 2 to 6 carbons, alkenyl-alkynyl of 4 to 6 carbons,alkynyl-alkenyl of 4 to 6 carbons, Cl, Br, I, OR₇, CH₂—NRR₇ or —COOR₁;

R₁ is independently H or alkyl of 1 to 6 carbons;

R₂ is independently H, alkyl of 1 to 6 carbons, F, Cl, Br, I, CF₃,fluoro substituted alkyl of 1 to 6 carbons, alkoxy of 1 to 6 carbons, oralkylthio of 1 to 6 carbons;

R₃ is independently alkyl of 1 to 6 carbons, F, Cl, Br, I, fluorosubstituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons,alkylthio of 1 to 6 carbons or benzyl;

m is an integer having the values 0 to 3;

R₄ is independently H, alkyl of 1 to 6 carbons, or F; fluorosubstitutedalkyl of 1 to 6 carbons, or halogen;

o is an integer having the values of 0 to 4;

R₇ is H, alkyl of 1 to 6 carbons, cycloalkyl of 3 to 6 carbons or C₁₋₆alkyl substituted cycloalkyl of 1 to 6 carbons, and

R₈ is H, alkyl of 1 to 6 carbons, —CH₂O(C₁₋₆-alkyl), CH₂OCO(C₁₋₆-alkyl)or a cation of a pharmaceutically acceptable base.

The present invention also relates to pharmaceutical compositionscomprising one or more of the compounds of Formulas 1 through 17 and tomethods of using such pharmaceutical compositions to treat the diseasesconditions which are normally treatable with retinoids. The inventionstill more advantageously relates to using the pharmaceuticalcompositions containing one or more compounds of Formulas 1 through 17for treatment of diseases or conditions where treatment with ancytochrome P450RAI1 or with a cytochrome P450RAI2 specific or selectiveinhibitor provides a therapeutic advantage.

BRIEF DESCRIPTION OF THE DRAWING

The FIGURE is a schematic representation of the P450RAI cell based assayutilized to evaluate the ability of a compound of to inhibit theCytochrome P450RAI enzyme.

BIOLOGICAL ACTIVITY, MODES OF ADMINISTRATION

P450RAI-1 and P450RAI-2 Cell-Based Inhibitor Assay:

The FIGURE shows a schematic diagram of the P450RAI-1 and P450RAI-2 cellbased assay. P450RAI-1 stably transfected HeLa cells, or P450RAI-2stably transfected HeLa cells, as applicable, are maintained in 100millimolar tissue culture dishes in Modified Eagle's Medium (MEM)containing 10% Fetal Bovine Serum (FBS) and 100 μg/ml hygromycin.Exponentially growing cells are harvested by incubating in trypsin.Cells are then washed with 1× Phosphate Buffered Saline (PBS) and platedin a 48-well plate at 5×10⁵ cells in 0.2 ml MEM medium containing 10%FBS and 0.05 μCi [³H]—RA in the presence or absence of increasingconcentrations of the test compounds. The compounds are diluted in 100%DMSO and then added in triplicate wells at either 10, 1 or 0.1 μM finalconcentration. As a positive control for RA metabolism inhibition, cellsare also incubated with ketoconazole at 100, 10 and 1 μM. Cells areincubated for 3 hours at 37° C. The retinoids are then extracted usingthe procedure of Bligh et al. (1959) Canadian Journal of Biochemistry37, 911-917, modified by using methylenechloride instead of chloroform.The publication Bligh et al. (1959) Canadian Journal of Biochemistry 37,911-917 is specifically incorporated herein by reference. The watersoluble radioactivity is quantified using a β-scintillation counter.IC₅₀ values represent the concentration of inhibitor required to inhibitall-trans-RA metabolism by 50 percent and are derived manually fromlog-transformed data. The IC₅₀ values obtained in this assay with boththe RAI-1 and RAI-2 enzymes for several compounds which are preferredfor use in the co-administration methods and formulations of the presentinvention are disclosed in Table 1 below. The data demonstrate that thetested compounds have specific or selective inhibitory activity foreither of the CP450RAI1 or of the CP450RAI2 enzyme. TABLE 1 P450R P450RAI-1 AI-2 Whole Whole RAR cell cell Compound EC₅₀/(EFFICACY)/K_(d) nMIC₅₀ IC₅₀ # Structures α β γ μM μM 2

NA¹558 NA 3439 NA 5577 0.03 >10 1

NA 2090 NA 3016 NA 3486 0.009 8 3

NA >10 K WA²(15) 520 NA (10) 6040 0.25 >10 4

NA >10 K WA (20) >10 K WA (15) >10 K 0.12 >10 13

NA 397 NA >10 K NA >10 K 0.06 8 12

NA >10 K NA >10 K NA >10 K 0.16 >10 11

NA >10 K NA >10 K NA >10 K 0.07 3 10

NA >10 K WA (15) >10 K NA >10 K 0.07 0.7 14

NA 5170 WA (10) 7400 WA (25) >10 K 0.7 >10 15

NA 8896 NA >10 K NA >10 K 0.6 >10 9

NA >10 K NA >10 K NA >10 K 0.12 >10 8

NA 957 WA (15) 4805 NA >10 K 0.05 >10 6

NA 3412 NA >10 K NA >10 K 0.06 4 7

NA >10 K NA >10 K NA >10 K 0.04 2 18

0.4 >10 20

2.9 >10 19

7 >10 45

118 (52) 9.9 18 (55) 76 31 (68) 255 0.7 >10 46

65 (67) 85 10 (75) 45 7 (68) 215 0.7 >10 47

WA (10) 2242 38 (59) 4473 125 (66) 1954 0.1 8.8 16

WA (˜5) 3083 WA (35) 810 WA (˜5) >10 K 1.3 >10 17

NA NA NA 2.5 >10 23

NA >10 K WA (40) >10 K WA (35) >10 K 0.008 0.5 49

5282 >10 K >10 K 0.05 >10 50

>10 K >10 K >10 K 0.1 >10 48

NA >10 K WA (40) >10 K WA (25) >10 K 0.7 10 52

NA >10 K WA (<5) >10 K NA >10 K 0.4 >10 51

NA >10 K WA (5) >10 K NA >10 K 0.2 >10 53

NA >10 K NA 3906 NA >10 K 0.5 5 54

NA 1808 NA 5088 NA >10 K 0.2 >10 28

NA >10 K NA >10 K NA 4200 0.25 >10 25

NA >10 K NA >10 K NA 317 0.1 >10 26

NA >10 K WA (25) >10 K NA 1123 0.018 5 29

NA >10 K NA >10 K NA >10 K 0.6 >10 27

NA 118 NA 1275 NA >10 K 0.028 >10 30

NA >10 K WA (15) >10 K NA >10 K 0.18 >10 41

NA >10 K NA >10 K WA (30) >10 K 0.016 >10 22

NA >10 K WA (15) >10 K NA >10 K 0.007 0.2 24

NA 8570 WA (30) 7188 NA 7747 0.035 5 32

NA >10 K NA >10 K NA >10 K 0.44 >10 33

NA 3252 WA (30) WA (10) >10 K >10 1 55

NA >10 K WA (35) >10 K WA (30) >10 K 1.4 >10 56

NA >10 K WA (30) >10 K NA >10 K 0.5 10 57

NA 6028 WA (50) 4979 WA (35) 7738 0.4 10 60

NA 6315 WA (60) 3957 WA (15) 8992 0.06 2.6 58

NA >10 K WA (25) 4614 NA >10 K 3.5 >10 59

NA >10 K WA (35) 2862 NA >10 K 1.2 >10 38

WA (10) >10 K NA >10 K NA >10 K 4 >10 39

NA >10 K NA >10 K NA >10 K 2.5 >10 40

NA >10 K NA >10 K NA >10 K 1.3 >10 42

NA >10 K WA (20) 2765 NA >10 K 0.06 2 43

WA (10) 2661* WA (60) 1158 WA (20) 3348* 0.01 0.7 44

NA >10 K NA 8169 NA >10 K 0.7 7.5 61

NA >10 K NA >10 K NA >10 K 0.22 8.1 62

NA >10 K NA >10 K NA >10 K 0.4 6.1 35

NA 1931 16 (80) 2089 126 (48) 2888 >10 0.5 36

NA >10 K WA (40) 3518 WA (15) 2084 >10 0.4 21

NA >10 K NA >10 K NA >10 K >10 0.7 5

NA >10 K 320 (55) 4536 WA (15) >10 K >10 0.45 31

NA >10 K WA (25) >10 K NA >10 K >10 0.6 34

NA 5648 WA (20) 3492 NA 8528 >10 0.12 37

WA (10) >10 K WA (70) 7015 WA (15) >10 K >10 0.5 63

NA >100 K 853 (37) 11 K NA >100 K >10 0.68NA¹ = Not Active;WA² = Weakly ActiveModes of Administration

The compounds of the invention are useful for curing or alleviating thesymptoms and conditions of the diseases and conditions which areresponsive to treatment by retinoids and/or to the organism's endogenousretinoic acid. Specifically by way of example and without limitation thecompounds of the invention are useful as regulators of cellproliferation and differentiation, and particularly as agents fortreating skin-related diseases, including, actinic keratoses, arsenickeratoses, inflammatory and non-inflammatory acne, psoriasis, ichthyosesand other keratinization and hyperproliferative disorders of the skin,eczema, atopic dermatitis, Darriers disease, lichen planus, preventionand reversal of glucocorticoid damage (steroid atrophy), as a topicalanti-microbial, as skin anti-pigmentation agents and to treat andreverse the effects of age and photo damage to the skin. The compoundsof the invention are also useful for the prevention and treatment ofcancerous and precancerous conditions, including, premalignant andmalignant hyperproliferative diseases such as cancers of the breast,skin, prostate, cervix, uterus, colon, bladder, esophagus, stomach,lung, larynx, oral cavity, blood and lymphatic system, metaplasias,dysplasias, neoplasias, leukoplakias and papillomas of the mucousmembranes and in the treatment of Kaposi's sarcoma. In addition, thecompounds of the invention can be used as agents to treat diseases ofthe eye, including, without limitation, proliferative vitreoretinopathy(PVR), retinal detachment, dry eye and other corneopathies, as well asfor the treatment and prevention of various cardiovascular diseases,including, without limitation, diseases associated with lipid metabolismsuch as dyslipidemias, prevention of post-angioplasty restenosis and asagents to increase the level of circulating tissue plasminogen activator(TPA). Other uses for the compounds of the invention include theprevention and treatment of conditions and diseases associated withhuman papilloma virus (HPV), including warts and genital warts, variousinflammatory diseases such as pulmonary fibrosis, ileitis, colitis andKrohn's disease, neurodegenerative diseases such as Alzheimer's disease,Parkinson's disease and stroke, improper pituitary function, includinginsufficient production of growth hormone, modulation of apoptosis,including both the induction of apoptosis and inhibition of T-Cellactivated apoptosis, restoration of hair growth, including combinationtherapies with the present compounds and other agents such asMinoxidil®, diseases associated with the immune system, including use ofthe present compounds as immunosuppressants and immunostimulants,modulation of organ transplant rejection and facilitation of woundhealing, including modulation of chelosis. The compounds of theinvention may also have use for treating type II non-insulin dependentdiabetes mellitus (NIDDM).

The compounds of this invention may be administered systemically ortopically, depending on such considerations as the condition to betreated, need for site-specific treatment, quantity of drug to beadministered, and numerous other considerations. Thus, in the treatmentof dermatoses, it will generally be preferred to administer the drugtopically, though in certain cases such as treatment of severe cysticacne or psoriasis, oral administration may also be used. Any commontopical formulation such as a solution, suspension, gel, ointment, orsalve and the like may be used. Preparation of such topical formulationsare well described in the art of pharmaceutical formulations asexemplified, for example, by Remington's Pharmaceutical Science, Edition17, Mack Publishing Company, Easton, Pa. For topical application, thecompounds could also be administered as a powder or spray, particularlyin aerosol form. If the drug is to be administered systemically, it maybe confected as a powder, pill, tablet or the like or as a syrup orelixir suitable for oral administration. For intravenous orintraperitoneal administration, the compound will be prepared as asolution or suspension capable of being administered by injection. Incertain cases, it may be useful to formulate these compounds byinjection. In certain cases, it may be useful to formulate thesecompounds in suppository form or as extended release formulation fordeposit under the skin or intramuscular injection.

Other medicaments can be added to such topical formulation for suchsecondary purposes as treating skin dryness; providing protectionagainst light; other medications for treating dermatoses; medicamentsfor preventing infection, reducing irritation, inflammation and thelike.

Treatment of dermatoses or any other indications known or discovered tobe susceptible to treatment by retinoic acid-like compounds, or tocontrol by naturally occurring retinoic acid will be effected byadministration of the therapeutically effective dose of one or morecompounds of the instant invention. A therapeutic concentration will bethat concentration which effects reduction of the particular condition,or retards its expansion. In certain instances, the compound potentiallymay be used in prophylactic manner to prevent onset of a particularcondition.

A useful therapeutic or prophylactic concentration will vary fromcondition to condition and in certain instances may vary with theseverity of the condition being treated and the patient's susceptibilityto treatment. Accordingly, no single concentration will be uniformlyuseful, but will require modification depending on the particularitiesof the disease being treated. Such concentrations can be arrived atthrough routine experimentation. However, it is anticipated that in thetreatment of, for example, acne, or similar dermatoses, that aformulation containing between 0.01 and 1.0 milligrams per milliliter offormulation will constitute a therapeutically effective concentrationfor total application. If administered systemically, an amount between0.01 and 5 mg per kg of body weight per day would be expected to effecta therapeutic result in the treatment of many diseases for which thesecompounds are useful.

In some applications pharmaceutical formulations containing theCP-450RAI inhibitory compounds may be co-administered with formulationscontaining retinoids. In such cases the dose of the cytochrome P450RAIinhibitory compounds is in the range of 0.01 and 5 mg per kg body weightper day.

GENERAL EMBODIMENTS AND SYNTHETIC METHODOLOGY

Definitions

The term alkyl refers to and covers any and all groups which are knownas normal alkyl and branched-chain alkyl. Unless specified otherwise,lower alkyl means the above-defined broad definition of alkyl groupshaving 1 to 6 carbons in case of normal lower alkyl, and 3 to 6 carbonsfor lower branch chained alkyl groups. A pharmaceutically acceptablesalt may be prepared for any compound used in accordance with theinvention having a functionality capable of forming a salt, for examplean acid functionality. A pharmaceutically acceptable salt is any saltwhich retains the activity of the parent compound and does not impartany deleterious or untoward effect on the subject to which it isadministered and in the context in which it is administered.

Pharmaceutically acceptable salts may be derived from organic orinorganic bases. The salt may be a mono or polyvalent ion. Of particularinterest are the inorganic ions, sodium, potassium, calcium, andmagnesium. Organic salts may be made with amines, particularly ammoniumsalts such as mono-, di- and trialkyl amines or ethanol amines. Saltsmay also be formed with caffeine, tromethamine and similar molecules.Where there is a nitrogen sufficiently basic as to be capable of formingacid addition salts, such may be formed with any inorganic or organicacids or alkylating agent such as methyl iodide. Preferred salts arethose formed with inorganic acids such as hydrochloric acid, sulfuricacid or phosphoric acid. Any of a number of simple organic acids such asmono-, di- or tri-acid may also be used.

Some compounds used in accordance with the present invention may havetrans and cis (E and Z) isomers. Unless specific orientation ofsubstituents relative to a double bond or a ring is indicated in thename of the respective compound, and/or by specifically showing in thestructural formula the orientation of the substituents relative to thedouble bond or ring the invention covers trans as well as cis isomers.

Some of the compounds used in accordance with the present invention maycontain one or more chiral centers and therefore may exist inenantiomeric and diastereomeric forms. The scope of the presentinvention is intended to cover all isomers per se, as well as mixturesof cis and trans isomers, mixtures of diastereomers and racemic mixturesof enantiomers (optical isomers) as well.

General Synthetic Methodology

The novel compounds used in accordance with the invention areencompassed by the general Formulas 1 through 17 provided above. In eachof these formulas a linker or tethering group designated Z covalentlyconnects an aromatic or heteroaromatic moiety designated A(R₂)—COOR₈,A(R₂)—W—COOR₈ or A(R₂)—CH₂—COOR₈ and another cyclic moiety which inaccordance with these formulas is a substituted phenyl, substitutedtetrahydronaphthalene, substituted dihydronaphthalene, substitutedchroman, substituted thiochroman or substituted tetrahydroquinolinemoiety.

Generally speaking compounds such as X₄-A(R₂)—W—COOR₈,X₄-A(R₂)—CH₂—COOR₈ and X₄-A(R₂)—COOR₈ are commercially available, or canbe made in accordance with the chemical literature, or with suchmodification of known chemical processes, or of chemical processesdisclosed herein which are within the skill of the practicing organicchemist. The group X₄ represents a reactive group, which is suitable forcoupling the X₄-A(R₂)—W—COOR₈, X₄-A(R₂)—CH₂—COOR₉ and X₄-A(R₂)—COOR₈compounds to a derivative of the substituted phenyl, substitutedtetrahydronaphthalene, substituted dihydronaphthalene, substitutedchroman, substituted thiochroman, or substituted tetrahydroquinolinemoiety so that as a result of the coupling the linker or tether moiety Zis formed. In many instances the group X₄ is a leaving group such ashalogen, or trifluoromethanesulfonyloxy, or a group capable ofparticipating in a Wittig or Horner Emmons reaction. In some instancesthe group X₄ is an ethynyl group capable of undergoing a couplingreaction with a leaving group (such as a halogen or atrifluoromethanesulfonyloxy group) attached to the substituted phenyl,substituted tetrahydronaphthalene, substituted dehydronaphthalene,substituted chroman, substituted thiochroman or substitutedtetrahydroquinoline moiety. The group X₄ can also represent an OH or anNH₂ group that forms an ester (COO) or amide (CONH) linker,respectively, when reacted with an activated carboxyl derivative of thesubstituted phenyl, substituted tetrahydronaphthalene, substituteddihydronaphthalene, substituted chroman, substituted thiochroman, orsubstituted tetrahydroquinoline moiety. The compounds of the formulasX₄-A(R₂)—W—COOR₈, X₄-A(R₂)—CH₂—COOR₈ and X₄-A(R₂)—COOR₈ are generallyreferred to in this description as “coupling reagents” or just“reagents” and the preparation of several examples of these couplingreagents is described in the specific examples below. Further examplesare the pyridyl, thienyl, furyl, pyridazine, pyrazine and otherheteroaryl analogs of the coupling reagents described in the specificexamples. These reagents can be obtained in accordance with the chemicalliterature, or with such modification of known chemical processes, or ofchemical processes disclosed herein which are within the skill of thepracticing organic chemist.

Still further in accordance with the general synthetic methodology toprovide the compounds of Formulas 1 through 17 a derivative of thesubstituted phenyl, substituted tetrahydronaphthalene, substituteddihydronaphthalene, substituted chroman, substituted thiochroman, orsubstituted tetrahydroquinoline moiety is synthesized first, having acovalently attached X₅ group. The X₅ group reacts with the X₄ group ofthe reagents X₄-A(R₂)—W—COOR₈, X₄-A(R₂)—CH₂—COOR₈ and X₄-A(R₂)—COOR₈ toform the linker designated Z in Formulas 1 through 17. The X₅ group isone that is capable of participating in a catalyzed coupling reaction,(such as an ethynyl group when X₄ is a leaving group), or a leavinggroup (such as halogen or trifluoromethanesulfonyloxy when X₄ is anethynyl group), or an activated carboxylic acid function (when X₄ is OHor NH₂). The X₅ group can also be an OH, SH or NH₂ group when the X₄group is an activated carboxylic acid function. Specific examples forsubstituted phenyl, substituted tetrahydronaphthalene, substituteddihydronaphthalene, substituted chroman, substituted thiochroman, orsubstituted tetrahydroquinoline intermediates having an X₅ functionalityare provided below, and are also available in the chemical scientificand patent literature.

Generally speaking, for reagents and reactions covalently joining asubstituted tetrahydronaphthalene, substituted dihydronaphthalene,substituted chroman, substituted thiochroman, or substitutedtetrahydroquinoline intermediate with a substituted aryl or heteroarylgroup, of the formulas A(R₂)—W—COOR₈, A(R₂)—CH₂—COOR₈ and A(R₂)—COOR₈ toform a compound including the linker designated Z, reference is made toU.S. Pat. Nos. 5,648,503; 5,723,666, 5,952,345, 6,252,090 and 6,313,107the specification of each of which are expressly incorporated herein byreference.

The substituted phenyl, substituted tetrahydronaphthalene, substituteddihydronaphthalene, substituted chroman, substituted thiochroman orsubstituted tetrahydroquinoline moiety of the novel compounds used inaccordance with the invention are derivatized in a manner to include thespecific substituents (such as for example the cycloalkyl substituents)encompassed within the scope of the invention, either before or afterthe A(R₂)—W—COOR₈, A(R₂)—CH₂—COOR₈ or A(R₂)—COOR₈ moiety has beenattached and the linker Z has formed, as illustrated by the belowdescribed specific examples.

The W—COOR₈, CH₂—COOR₈ or COOR₈ moiety of the compounds of Formulas 1through 17 can be modified in order to obtain still further novelcompounds. One such modification is saponification of compounds wherethe R₈ group is an alkyl, CH₂O(C₁₋₆-alkyl) or CH₂OCO(C₁₋₆-alkyl) group.Another modification is esterification of the carboxylic acid functionwhen the R₈ group is H or a cation. Such saponification andesterification reactions are well known in the art and within the skillof the practicing organic chemist.

SPECIFIC EMBODIMENTS

With reference to the symbol A in Formulas 1 through 17, the preferrednovel compounds used in accordance with the present invention are thosewhere A is phenyl, naphthyl, pyridyl, thienyl or furyl. Even morepreferred are compounds where A is phenyl. As far as substitutions onthe A (phenyl) and A (pyridyl) groups are concerned, compounds areusually preferred where the phenyl group is 1,4 (para) substituted andwhere the pyridine ring is 2,5 substituted. (Substitution in the 2,5positions in the “pyridine” nomenclature corresponds to substitution inthe 6-position in the “nicotinic acid” nomenclature.) In the presentlypreferred novel compounds used in accordance with the invention eitherthere is no R₂ substituent on the A group, or the R₂ substituent ispreferably a fluoro group that is preferably located on the aromaticcarbon adjacent (ortho) to the carbon bearing the W—COOR₈, CH₂—COOR₈ orCOOR₈ group.

As far as the W—COOR₈ moiety is concerned, the variable W preferablyrepresents —CH═CH—, —CR₅═CH—, CH═CR₅— (cinnamic acid derivatives) C(R₅)₂or CHR₅ where R₅ is preferably methyl. For the R₈ group H, lower alkylof 1 to 3 carbons, —CH₂O(C₁₋₃-alkyl) and —CH₂OCO(C₁₋₃-alkyl) groups arepreferred, as well as the pharmaceutically acceptable salts of the freeacids when R₈ is H. Among the lower alkyl, —CH₂O(C₁₋₃-alkyl) and—CH₂OCO(C₁₋₃-alkyl) groups methyl, ethyl, CH₂OCH₃ and CH₂OCOCH₃respectively, are presently most preferred.

The linker group Z in all of the novel compounds used in accordance withthe invention is preferably ethynyl, (—C≡C—), ester (CO—O), or ureido(NHCONH). Moreover for chroman, thichroman and tetrahydroquinolinederivatives the linker Z is preferably attached to the 6 position (e.g.see Formula 1). For tetrahydronaphthalene and dihydronaphthalenederivatives the linker Z is preferably attached to the to the 6 positionas such positions are numbered in Formulas 2 and 11.

The R₁ group is preferably methyl when it serves as a substituentattached to a carbon of the chroman, thiochroman, tetrahydroquinoline,tetrahydronaphthalene or dihydronaphthalene nucleus and is preferablyhydrogen when it forms part of a linker Z.

The aromatic portion of the chroman, thiochroman, tetrahydroquinoline,tetrahydronaphthalene or dihydronaphthalene nuclei of the compounds ofthe present invention is either preferably not substituted with an R₃group (the variable m is zero (0)), or R₃ is alkyl or halogen. Thenon-aromatic portion of the chroman, thiochroman, tetrahydroquinoline,tetrahydronaphthalene or dihydronaphthalene nuclei of the compounds ofthe present invention is either preferably not substituted with an R₄group (the variable o is zero (0)), or (R₄)_(o) represents methylgroups, still more preferably geminal dimethyl or geminal diethyl groupsattached to the 2-position of the chroman nucleus.

Structures of the most preferred compounds of the invention are shown inTable 1. Whereas most of the compounds shown in Table 1 are carboxylicacids, it should be understood that the C₁₋₃ alkyl esters, CH₂OCH₃ andCH₂OCOCH₃ esters and the pharmaceutically acceptable salts of thesecompounds are also preferred.

The compounds of the invention can be synthesized by applying thegeneral synthetic methodology described above, and by such modificationsof the hereinafter described specific synthetic routes which will becomereadily apparent to the practicing synthetic organic chemist in light ofthis disclosure and in view of general knowledge available in the art.The hereinafter disclosed specific reaction schemes are directed to thesynthesis of exemplary and preferred compounds of the invention. Whereaseach of the specific and exemplary synthetic routes shown in theseschemes may describe specific compounds of the invention only within thescope of one or two of the general Formulas 1 through 17, the syntheticprocesses and methods used therein are adaptable within the skill of thepracticing organic chemist and can be used with such adaptation for thesynthesis of compounds of the invention which are not specificallydescribed herein as examples.

SPECIFIC EXAMPLES

The reactions schemes provided below together with the applicableexperimental descriptions disclose the presently preferred syntheticroutes for preparing the preferred compounds of the invention.Synthetic Procedures for Preparing Coupling Reagents

General Procedure A Methyl-2-(4-iodophenyl)propionate Reagent 1

A stirred, cooled (−78° C.) solution of methyl-4-iodophenyl acetate(described in U.S. Pat. No. 6,252,090, incorporated herein by reference;2.77 g, 10 mmol) in anhydrous tetrahydrofuran (20 mL) was treated with a1.5M solution of lithium diisopropyl amide in tetrahydrofuran andcyclohexane (8 mL, 12 mmol). The reaction mixture was allowed to warm to0° C. over 40 minutes, cooled again to −78° C. and treated with methyliodide (0.75 mL, 12 mmol). The reaction mixture was allowed to warm toroom temperature over 1 h. It was then quenched with saturated aqueousammonium chloride solution, diluted with water and extracted withdiethyl ether. The combined organic phase was washed with brine (×1),dried over anhydrous magnesium sulfate, filtered and evaporated in vacuoto afford the title product as a yellow oil (2.7 g, 92.7%).

¹H NMR (300 MHz, CDCl₃): δ 7.66 (d, 2H, J=8.5 Hz), 7.06 (d, 2H, J=8.5Hz), 3.70-3.66 (m, 1H), 3.67 (s, 3H), 1.49 (d, 3H, J=7.0 Hz).

Methyl-2-(4-idophenyl)-2-methyl propionate Reagent 2

Following General Procedure A and usingmethyl-2-(4-iodophenyl)propionate (1.45 g, 5 mmol), lithium diisopropylamide (1.5M in tetrahydrofuran and cyclohexane, 4 mL, 6 mmol),tetrahydrofuran (15 mL) and methyl iodide (0.5 mL, 8 mmol), the titlecompound was obtained as an oil (1.5 g, 98%).

¹H NMR (300 MHz, CDCl₃): δ 7.66 (d, 2H, J=8.7 Hz), 7.11 (d, 2H, J=8.7Hz), 3.66 (s, 3H), 1.58 (s, 6H).

4-Iodo-benzyl alcohol

A stirred, cooled (−78° C.) solution of ethyl-4-iodo-benzoate (availablefrom Lancaster, 12.9 g, 45 mmol) in anhydrous dichloromethane (100 mL)under argon was treated with a 1M solution of di-isobutyl aluminumhydride in dichloromethane (100 mL, 100 mmol). The reaction mixture wasallowed to warm to 0° C. in 1.5 h, quenched with saturated aqueousammonium chloride solution and the resulting emulsion was filtered overa bed of celite. The phases in the filtrate were separated and theaqueous phase was extracted with dichloromethane (×1). The combinedorganic phase was dried over anhydrous sodium sulfate, filtered andevaporated in vacuo to afford the title product as a white solid (9 g,85%).

¹H NMR (300 MHz, CDCl₃): δ7.65 (d, 2H, J=7.6 Hz), 7.05 (d, 2H, J=7.6Hz), 4.57 (s, 2H), 2.40 (br s, 1H).

4-Iodo-benzaldehyde

A solution of 4-iodobenzyl alcohol (9 g, 38.29 mmol) in dichloromethane(90 mL) and acetonitrile (10 mL) was treated sequentially with 4 Amolecular sieves powder (9 g), tetra-n-propyl ammoniumperruthenate (0.13g) and N-methyl morpholine-N-oxide (9 g, 76.6 mmol). After stirring atambient temperature for 2 h, the reaction mixture was diluted withhexane and subjected to flash column chromatography over silica gel(230-400 mesh) using 6-10% ethyl acetate in hexane as the eluent toafford the title compound (2.5 g pure and 4 g ˜95% pure, 73%).

¹H NMR (300 MHz, CDCl₃): δ 9.96 (s, 1H), 7.92 (d, 2H, J=8.5 Hz), 7.59(d, 2H, J=8.5 Hz)

Ethyl-4-iodo-cinnamate Reagent 3

A stirred, cooled (−78° C.) solution of triethylphosphonoacetate (11.1mL, 56 mmol) in anhydrous tetrahydrofuran (100 mL) was treated with a1.6M solution of n-butyl lithium in hexanes (27 mL, 43.75 mmol). After10 min, the reaction mixture was cannulated into a cooled (−78° C.)solution of 4-iodo-benzaldehyde (6.5 g, 28 mmol) in tetrahydrofuran (20mL). The reaction mixture was allowed to warm to 0° C. over 1 h. It wasquenched with saturated aqueous ammonium chloride solution and extractedwith diethyl ether (×2). The combined organic phase was dried overanhydrous magnesium sulfate, filtered and evaporated in vacuo to affordan oil that was subjected to flash column chromatography over silica gel(230-400 mesh) using 6-8% ethyl acetate in hexane as the eluent toafford the title compound (2.7 g pure, 3.2 g 95% pure, 69%).

¹H NMR (300 MHz, CDCl₃): δ 7.70 (d, 2H, J=8.5 Hz), 7.57 (d, 1H, J=15.8Hz), 7.21 (d, 2H, J=8.5 Hz), 6.43 (d, 1H, J=15.8 Hz), 4.25 (q, 2H, J=7.1Hz), 1.33 (t, 3H, J=7.1 Hz).

4-Iodo-cinnamic acid

A solution of ethyl-4-iodo-cinnamate (3.2 g, 10.5 mmol) in methanol (25mL), tetrahydrofuran (25 mL) and water (15 mL) was treated with lithiumhydroxide monohydrate (4.2 g, 100 mmol) and the resulting reactionmixture was stirred at ambient temperature over 2 days. The volatileswere evaporated in vacuo and the residue was neutralized with saturatedaqueous ammonium chloride solution. The precipitated solid was filtered,washed with water and hexane and dried to afford the title product as awhite solid (2.9 g, 91%). It was used as such for the next step.

Methyl-4-iodo-cinnamate Reagent 4

A stirred, cooled (ice bath) solution of 4-iodo-cinnamic acid inmethanol was treated with a solution of diazomethane in diethyl ether.The reaction mixture was allowed to warm to ambient temperature, thevolatiles were evaporated in vacuo to afford the title compound.

3-(4-Iodo-phenyl)-but-2Z-enoic acid ethyl ester Reagent 5

A stirred, cooled (−78° C.) solution of triethyl-2-phosphonoacetate(4.55 g, 20 mmol) in anhydrous tetrahydrofuran (10 mL) was treated witha 1.6M solution of n-butyl lithium in hexanes (12.8 mL, 20.5 mmol).After 30 min, a solution of 4-iodo-acetophenone (2.5 g, 10 mmol) intetrahydrofuran (5 mL) was cannulated into the reaction mixture. After 4h, it was quenched with saturated aqueous ammonium chloride solution andextracted with diethyl ether (×2). The combined organic phase was driedover anhydrous magnesium sulfate, filtered and evaporated in vacuo toafford an oil that was subjected to flash column chromatography oversilica gel (230-400 mesh) using 5-10% ethyl acetate in hexane as theeluent, followed by preparative normal phase HPLC to afford the titlecompound (0.53 g, 15%).

¹H NMR (300 MHz, CDCl₃): δ 7.67 (d, J=8.2 Hz, 2H), 6.94 (d, J=8.2 Hz,2H), 5.91 (s, 1H), 4.01 (q, J=7.1 Hz, 2H), 2.14 (s, 6H), 1.12 (t, J=7.1Hz, 3H).

3-Iodo-benzaldehyde

A solution of 3-iodobenzyl alcohol (Aldrich, 4.72 g, 20 mmol) indichloromethane (50 mL) and acetonitrile (5 mL) was treated sequentiallywith 4 A molecular sieves powder (5 g), tetra-n-propylammoniumperruthenate (0.1 g) and N-methyl morpholine-N-oxide (2.34 g, 40mmol). After stirring at ambient temperature for 3 h, the reactionmixture was diluted with hexane and subjected to flash columnchromatography over silica gel (230-400 mesh) using 6-10% ethyl acetatein hexane as the eluent to afford the title compound (3.7 g, 80%). Itwas used as such for the next step.

Ethyl-3-iodo-cinnamate Reagent 6

A stirred, cooled (−78° C.) solution of triethylphosphonoacetate (11.44g, 51 mmol) in anhydrous tetrahydrofuran (100 mL) was treated with a1.6M solution of n-butyl lithium in hexanes (30 mL, 48 mmol). After 10min, the reaction mixture was cannulated into a cooled (−78° C.)solution of 4-iodo-benzaldehyde (3.7 g, 16 mmol) in tetrahydrofuran (20mL). The reaction mixture was allowed to warm to 0° C. over 1 h. It wasquenched with saturated aqueous ammonium chloride solution and extractedwith diethyl ether (×2). The combined organic phase was dried overanhydrous magnesium sulfate, filtered and evaporated in vacuo to affordan oil that was subjected to flash column chromatography over silica gel(230-400 mesh) using 8-10% ethyl acetate in hexane as the eluent toafford the title compound (4.6 g, 95%).

¹H NMR (300 MHz, CDCl₃): δ 7.83 (s, 1H), 7.65 (dd, 1H, J=7.9, 2 Hz),7.53 (d, 1H, J=15.8 Hz), 7.43 (dd, 1H, J=7.6, 2 Hz), 7.07 (dd, 1H,J=7.6, 7.9 Hz), 6.38 (d, 1H, J=15.8 Hz), 4.24 (q, 2H, J=6.9 Hz), 1.34(t, 3H, J=6.9 Hz).

(E)-3-(4-Iodo-phenyl)-2-methyl-acrylic acid ethyl ester Reagent 7

A stirred, cooled (−78° C.) solution of triethyl-2-phosphonopropionate(10 g, 41.9 mmol) in anhydrous tetrahydrofuran (100 mL) was treated witha 1.6M solution of n-butyl lithium in hexanes (25 mL, 40 mmol). After 10min, the reaction mixture was cannulated into a cooled (−78° C.)solution of 4-iodo-benzaldehyde (4.66 g, 20 mmol) in tetrahydrofuran (25mL). After 30 minutes, it was quenched with saturated aqueous ammoniumchloride solution and extracted with diethyl ether (×2). The combinedorganic phase was dried over anhydrous magnesium sulfate, filtered andevaporated in vacuo to afford an oil that was subjected to flash columnchromatography over silica gel (230-400 mesh) using 9-10% ethyl acetatein hexane as the eluent to afford the title compound (6.3 g, 99%).

¹H NMR (300 MHz, CDCl₃): δ 7.71 (d, 2H, J=8.4 Hz), 7.58 (s, 1H), 7.12(d, 2H, J=8.4 Hz), 4.27 (q, 2H, J=7.2 Hz), 2.08 (d, 3H, J=1.5 Hz), 1.35(t, 3H, J=7.2 Hz).

2-Chloro-3-(4-iodo-phenyl)-acrylic acid ethyl ester Reagent 8

A stirred, cooled (−78° C.) solution ofchloro-(dipropyl-phosphinoyl)-acetic acid ethyl ester (6.1 g, 23.5 mmol)in anhydrous tetrahydrofuran (70 mL) was treated with a 1.6M solution ofn-butyl lithium in hexanes (14 mL, 22 mmol). After 10 min the reactionmixture was cannulated into a cooled (−78° C.) solution of4-iodo-benzaldehyde (2.61 g, 11.2 mmol) in tetrahydrofuran (25 mL).After 30 minutes, it was quenched with saturated aqueous ammoniumchloride solution and extracted with diethyl ether (×2). The combinedorganic phase was dried over anhydrous magnesium sulfate, filtered andevaporated in vacuo to afford an oil that was subjected to flash columnchromatography over silica gel (230-400 mesh) using 4-5% ethyl acetatein hexane as the eluent to afford the title compound as a 1:1 mixture ofE and Z isomers (3.6 g, 95%).

4-Iodo-tert-butyl phenyl acetate Reagent 10

A solution of 4-iodo phenyl acetic acid (Lancaster, 1.31 g, 5 mmol) inanhydrous toluene (10 mL) was heated to 80° C. and treated with asolution of N,N-dimethyl formamide di-1-butyl acetal. After 2 h thereaction mixture was cooled to ambient temperature and subjected toflash column chromatography on silica gel (23-400 mesh) using 10% ethylacetate in hexane as the eluent to afford the title compound (0.7 g,44%).

¹H NMR (300 MHz, CDCl₃): δ 7.62 (d, 2H, J=8.2 Hz), 7.01 (d, 2H, J=8.2Hz), 3.45 (s, 2H), 1.43 (s, 9H).

(2-Fluoro-4-iodo-phenyl)-acetic acid acetoxymethyl ester Reagent 11

A solution of 2-fluoro-4-iodo phenyl acetic acid (described in U.S. Pat.No. 6,252,090, incorporated herein by reference; 0.82 g, 2.93 mmol) inanhydrous acetonitrile (10 mL) was treated with N,N-diisopropyl ethylamine (1.27 mL, 7.32 mmol) followed by acetoxy methyl bromide/bromomethylacetate (0.896 g, 5.86 mmol) and the resulting reaction mixturewas stirred overnight at ambient temperature. The volatiles wereevaporated in vacuo and the residue was diluted with water and extractedwith diethyl ether (×2). The combined organic phase was dried overanhydrous magnesium sulfate, filtered and evaporated in vacuo to an oilthat was subjected to flash column chromatography over silica gel(230-400 mesh) using 10-20% ethyl acetate in hexane as the eluent toafford the title compound as an oil (0.75 g, 72%). ¹H NMR (300 MHz,CDCl₃): 7.42 (m, 2H), 6.97 (dd, J=8.0 & 8.0 Hz, 1H), 5.73 (s, 2H), 3.65(s, 2H), 2.08 (s, 3H).

(2-Fluoro-4-iodo-phenyl)-acetic acid 2-trimethylsilanyl-ethyl esterReagent 12

A solution of 2-fluoro-4-iodo phenyl acetic acid (0.3 g, 1.07 mmol) and2-(trimethylsilyl)ethanol (0.28 mL, 1.95 mmol) in anhydrousdichloromethane (5 mL) was treated with 4-(dimethylamino)pyridine (0.275g, 2.3 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (0.37 g, 1.95 mmol) and the resulting reaction mixture wasstirred at ambient temperature overnight. The reaction mixture was thensubjected to flash column chromatography using 5% ethyl acetate inhexane as the eluent to afford the title compound as a white solid (0.37g, 91%).

¹H NMR (300 MHz, CDCl₃): 7.44 (m, 2H), 7.02 (dd, J=8.0, 8.0 Hz, 1H),4.20 (t, J=8.5 Hz, 2H), 3.59 (s, 2H), 0.98 (t, J=8.5 Hz, 2H), 0.02 (s,9H).

Synthesis of Preferred Embodiments

General Procedure B2-{4-[(8-Cyclopropyl-3,4-dihydro-4,4-dimethylspiro[2H-1-benzopyran-2,1′-cyclopropane]-6-yl)ethynyl]-phenyl}-propionicacid methyl ester Intermediate 1

A solution of8-cyclopropyl-6-ethynyl-3,4-dihydro-4,4-dimethylspiro[2H-1-benzopyran-2,1′-cyclopropane](described in U.S. Pat. No. 6,252,090; 0.068 g, 0.27 mmol), andmethyl-2-(4-iodo phenyl)propionate (Reagent 1, 0.086 g, 0.3 mmol) intriethyl amine (3 mL), was treated with copper(I)iodide (0.028 g, 0.15mmol) and sparged with argon for 5 minutes.Dichlorobis(triphenylphosphine)palladium(II) (0.057 g, 0.08 mmol) wasadded and the reaction mixture was stirred overnight at roomtemperature. It was diluted with diethyl ether and filtered over a bedof celite. The filtrate was evaporated in vacuo to brown oil that wassubjected to flash column chromatography over silica gel (230-400 mesh)to afford the title compound as an oil (0.072 g, 56%).

¹H NMR (300 MHz, CDCl₃): δ 7.46 (d, 2H, J=8.4 Hz), 7.29 (d, 1H, J=2.1Hz), 7.25 (d, 2H, J=8.4 Hz), 6.80 (d, 1H, J=2.1 Hz), 3.68 (q, 1H, J=7.2Hz), 3.66 (s, 3H), 2.02-1.90 (m, 1H), 1.90 (s, 2H), 1.49 (d, 3H, J=7.2Hz), 1.39 (s, 6H), 1.03-0.99 (m, 2H), 0.90-0.83 (m, 2H), 0.68-0.59 (m,4H).

2-{4-[(8-Cyclopropyl-3,4-dihydro-4,4-dimethylspiro[2H-1-benzopyran-2,1′-cyclopropane]-6-yl)ethynyl]-phenyl}-propionicacid Compound 1

A solution of2-{4-[(8-cyclopropyl-3,4-dihydro-4,4-dimethylspiro[2H-1-benzopyran-2,1′-cyclopropane]-6-yl)ethynyl]-phenyl}-propionicacid methyl ester (Intermediate 1, 0.072 g, 0.174 mmol) in methanol (5mL) was treated with a 1M solution of sodium hydroxide (1 mL, 1 mmol)and the resulting reaction mixture was heated at 55° C. for 4 h. Thereaction mixture was cooled to ambient temperature and the volatileswere evaporated in vacuo to a residue that was diluted with 10%hydrochloric acid till neutral and extracted with ethyl acetate. Theorganic phase was washed with water and brine, dried over anhydrousmagnesium sulfate, filtered and evaporated in vacuo to afford the titleproduct as a white solid after flash column chromatography over silicagel (230-400 mesh) (0.04 g, 57%).

¹H NMR (300 MHz, CDCl₃): δ 7.46 (d, 2H, J=8.1 Hz), 7.30-7.25 (m, 3H),6.80 (d, 1H, J=1.8 Hz), 3.74 (q, 1H, J=7.2 Hz), 1.99-1.96 (m, 1H), 1.91(s, 2H), 1.51 (d, 3H, J=7.2 Hz), 1.39 (s, 6H), 1.04-0.99 (m, 2H),0.90-0.83 (m, 2H), 0.68-0.59 (m, 4H).

2-{4-[(8-Cyclopropyl-3,4-dihydro-4,4-dimethylspiro[2H-1-benzopyran-2,1′-cyclopropane]-6-yl)ethynyl]-phenyl}-2-methyl-propionicacid methyl ester Intermediate 2

Following General Procedure B and using8-cyclopropyl-6-ethynyl-3,4-dihydro-4,4-dimethylspiro[2H-1-benzopyran-2,1′-cyclopropane](0.096 g, 0.38 mmol), methyl-2-(4-iodo phenyl)-2-methyl-propionate(Reagent 2, 0.127 g, 0.41 mmol), triethyl amine (3 mL), copper(I)iodide(0.040 g, 0.21 mmol) and dichlorobis(triphenylphosphine)palladium(II)(0.080 g, 0.11 mmol) followed by flash column chromatography over silicagel (230-400 mesh), the title compound was obtained as an oil (0.046 g,47%).

¹H NMR (300 MHz, CDCl₃): δ 7.39 (d, 2H, J=8.4 Hz), 7.23-7.20 (m, 3H),6.72 (d, 1H, J=2.1 Hz), 3.58 (s, 3H), 1.92-1.84 (m, 1H), 1.84 (s, 2H),1.51 (s, 6H), 1.33 (s, 6H), 0.97-0.92 (m, 2H), 0.83-0.76 (m, 2H),0.59-0.52 (m, 4H).

2-{4-[(8-Cyclopropyl-3,4-dihydro-4,4-dimethylspiro[2H-1-benzopyran-2,1′-cyclopropane]-6-yl)ethynyl]-phenyl}-2-methyl-propionicacid Compound 2

A solution of2-{4-[(8-cyclopropyl-3,4-dihydro-4,4-dimethylspiro[2H-1-benzopyran-2,1′-cyclopropane]-6-yl)ethynyl]-phenyl}-2-methyl-propionicacid methyl ester (Intermediate 2, 0.046 g, 0.107 mmol) in methanol (5mL) was treated with a 1M solution of sodium hydroxide (1.2 mL, 1.2mmol) and the resulting reaction mixture was heated at 55° C. for 4 h.The reaction mixture was cooled to ambient temperature and the volatileswere evaporated in vacuo to a residue that was neutralized with 10%hydrochloric acid and extracted with ethyl acetate. The organic phasewas washed with water and brine, dried over anhydrous magnesium sulfate,filtered and evaporated in vacuo to afford the title product as a whitesolid after flash column chromatography over silica gel (230-400 mesh)(0.067 g, 89%).

¹H NMR (300 MHz, CDCl₃): δ 7.47 (d, 2H, J=8.1 Hz), 7.36 (d, 2H, J=8.1Hz), 7.30 (d, 1H, J=2.1 Hz), 6.80 (d, 1H, J=2.1 Hz), 1.99-1.91 (m, 1H),1.91 (s, 2H), 1.60 (s, 6H), 1.40 (s, 6H), 1.04-0.99 (m, 2H), 0.90-0.84(m, 2H), 0.69-0.59 (m, 4H).

(E)-3-{4-[8-Cyclopropyl-3,4-dimethylspiro[2H-1-benzopyran-2,1′-cycloproipane]-6-yl]ethynyl-phenyl}-2-methyl-acrylicacid ethyl ester Intermediate 3

Following General Procedure B and using8-cyclopropyl-6-ethynyl-3,4-dihydro-4,4-dimethylspiro[2H-1-benzopyran-2,1′-cyclopropane](0.077 g, 0.3 mmol), (E)-3-(4-iodo-phenyl)-2-methyl-acrylic acid ethylester (Reagent 7, 0.106 g, 0.23 mmol), triethyl amine (3 mL),copper(I)iodide (0.029 g, 0.115 mmol) anddichlorobis(triphenylphosphine)palladium(II) (0.064 g, 0.09 mmol)followed by flash column chromatography over silica gel (230-400 mesh),the title compound was obtained (0.06 g, 45%).

¹H NMR (300 MHz, CDCl₃): δ 7.65 (d, 1H, J=1.5 Hz), 7.52 (d, 2H, J=8.7Hz), 7.37 (d, 2H, J=8.7 Hz), 7.32 (d, 1H, J=1.8 Hz), 6.82 (d, 1H, J=1.8Hz), 4.27 (q, 2H, J=7.2 Hz), 2.14 (d, 3H, J=1.5 Hz), 1.99 (m, 1H), 1.91(s, 2H), 1.40 (s, 12H), 1.35 (t, 3H, J=7.2 Hz), 1.04-1.00 (m, 2H),0.91-0.84 (m, 2H), 0.69-0.59 (m, 4H).

(E)-3-{4-[8-Cyclopropyl-3,4-dimethylspiro[2H-1-benzopyran-2,1′-cyclopropane]-6-yl]ethynyl-phenyl}-2-methyl-acrylicacid Compound 3

A solution of(E)-3-{4-[8-cyclopropyl-3,4-dimethylspiro[2H-1-benzopyran-2,1′-cyclopropane]-6-yl]ethynyl-phenyl}-2-methyl-acrylicacid ethyl ester (Intermediate 3, 0.06 g, 0.13 mmol) in ethanol (2 mL)was treated with a 1M solution of sodium hydroxide (0.5 mL, 0.5 mmol)and the resulting reaction mixture was heated at 55° C. for 4 h. Thereaction mixture was cooled to ambient temperature and the volatileswere evaporated in vacuo to a residue that was neutralized with 5%hydrochloric acid and extracted with ethyl acetate. The organic phasewas washed with water and brine, dried over anhydrous magnesium sulfate,filtered and evaporated in vacuo to afford the title product as a yellowsolid after flash column chromatography over silica gel (230-400 mesh)(0.044 g, 82%).

¹H NMR (300 MHz, CDCl₃): δ 7.81 (d, 1H, J=1.5 Hz), 7.54 (d, 2H, J=8.4Hz), 7.41 (d, 2H, J=8.4 Hz), 7.33 (d, 1H, J=2.1 Hz), 6.83 (d, 1H, J=2.1Hz), 2.17 (d, 3H, J=1.5 Hz), 2.00 (m, 1H), 1.92 (s, 2H), 1.41 (s, 12H),1.05-1.00 (m, 2H), 0.91-0.84 (m, 2H), 0.69-0.60 (m, 4H).

(Z)-2-Chloro-3-{4-[8-cyclopropyl-3,4-dimethylspiro[2H-1-benzopyran-2,1′-cyclopropane]-6-yl]ethynyl}-acrylicacid ethyl ester Intermediate 4

Following General Procedure B and using8-cyclopropyl-6-ethynyl-3,4-dihydro-4,4-dimethylspiro[2H-1-benzopyran-2,1′-cyclopropane](0.11 g, 0.436 mmol), (E,Z)-2-chloro-3-(4-iodo-phenyl)-acrylic acidethyl ester (Reagent 8, 0.162 g, 0.48 mmol), triethyl amine (3 mL),copper(I)iodide (0.041 g, 0.21 mmol) anddichlorobis(triphenylphosphine)palladium(II) (0.092 g, 0.13 mmol)followed by flash column chromatography over silica gel (230-400 mesh),and preparative normal phase HPLC using 5% ethyl acetate in hexane asthe mobile phase, the title compound was obtained (0.09 g, 45%).

¹H NMR (300 MHz, CDCl₃): δ 7.88 (s, 1H), 7.83 (d, 2H, J=8.1 Hz), 7.55(d, 2H, J=8.1 Hz), 7.33 (d, 1H, J=2.1 Hz), 6.82 (d, 1H, J=2.1 Hz), 4.36(q, 2H, J=6.9 Hz), 1.99 (m, 1H), 1.92 (s, 2H), 1.41 (s, 12H), 1.39 (t,3H, J=6.9 Hz), 1.05-1.00 (m, 2H), 0.91-0.84 (m, 2H), 0.70-0.60 (m, 4H).

(Z)-2-Chloro-3-{4-[8-cyclopropyl-3,4-dimethylspiro[2H-1-benzopyran-2,1′-cyclopropane]-6-yl]ethynyl}-acrylicacid Compound 4

A solution of(Z)-2-chloro-3-{4-[8-cyclopropyl-3,4-dimethylspiro[2H-1-benzopyran-2,1′-cyclopropane]-6-yl]ethynyl}-acrylicacid ethyl ester (Intermediate 4, 0.09 g, 0.19 mmol) in ethanol (1 mL)and tetrahydrofuran (3 mL) was treated with a 1M solution of sodiumhydroxide (0.7 mL, 0.7 mmol) and the resulting reaction mixture washeated at 55° C. overnight. The reaction mixture was cooled to ambienttemperature and the volatiles were evaporated in vacuo to a residue thatwas neutralized with 10% hydrochloric acid and extracted with ethylacetate. The organic phase was washed with water and brine, dried overanhydrous magnesium sulfate, filtered and evaporated in vacuo to affordthe title product as a yellow solid after flash column chromatographyover silica gel (230-400 mesh) (0.08 g, 95%).

¹H NMR (300 MHz, CDCl₃): δ 7.74 (s, 1H), 7.55 (d, 2H, J=8.1 Hz), 7.31(d, 2H, J=8.1 Hz), 7.20 (d, 1H, J=1.8 Hz), 6.70 (d, 1H, J=1.8 Hz), 1.86(m, 1H), 1.79 (s, 2H), 1.27 (s, 12H), 0.94-0.81 (m, 2H), 0.77-0.71 (m,2H), 0.59-0.47 (m, 4H).

6-Amino-8-cyclopropyl-3,4-dihydro-4,4-dimethylspiro[2H-1-benzopyran-2,1′-cyclopropane] Intermediate 5

A solution of6-bromo-8-cyclopropyl-3,4-dihydro-4,4-dimethylspiro[2H-1-benzopyran-2,1′-cyclopropane](described in U.S. Pat. No. 6,252,090; 0.322 g, 1.049 mmol),benzophenone imine (Fluka 0.093 mL, 1.15 mmol), sodium-tert-butoxide(0.142 g, 1.47 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.023 g,0.025 mmol) and (S)-(−)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl(Aldrich, 0.047 g, 0.075 mmol) in 7 mL of anhydrous toluene was spargedwith argon and heated at 95° C. for 36 h. The reaction mixture wascooled to ambient temperature, quenched with water and extracted withethyl acetate. The combined organic phase was washed with water andbrine, dried over anhydrous magnesium sulfate, filtered and evaporatedin vacuo to afford a thick brown oil (0.73 g). The oil was dissolved intetrahydrofuran (3.5 mL) and treated with 2M hydrochloric acid (1.7 mL).After stirring at ambient temperature for 20 minutes, 0.5 mL of 2Mhydrochloric acid and 40 mL of water were added and the reaction mixturewas extracted with hexane:ethyl acetate (2:1, 3×60 mL). The aqueousphase was neutralized with potassium hydroxide and extracted withdichloromethane (3×50 mL). The combined organic phase was dried overanhydrous magnesium sulfate, filtered and evaporated in vacuo to affordan oil that on flash column chromatography over silica gel (230-400mesh) afforded the title product as a brown solid (0.15 g, 58%).

¹H NMR (300 MHz, CDCl₃): δ 6.46 (d, 1H, J=2.7 Hz), 6.01 (d, 1H, J=2.7Hz), 3.28 (br s, 2H), 2.02-1.93 (m, 1H), 1.87 (s, 2H), 1.34 (s, 6H),0.97-0.93 (m, 2H), 0.85-0.78 (m, 2H), 0.61-0.59 (m, 4H).

4-{3-[8-Cyclopropyl-3,3-dihydro-4,4-dimethylspiro(2H-1-benzopyran-2,2′-cyclopropane)-6-yl]-ureido}-benzoicacid methyl ester Intermediate 6

A solution of 4-isocyanato-benzoic acid methyl ester (Aldrich, 0.17 g,0.97 mmol) in anhydrous toluene (5 mL) was treated with a solution of6-amino-8-cyclopropyl-3,4-dihydro-4,4-dimethylspiro[2H-1-benzopyran-2,1′-cyclopropane](Intermediate 5, 0.07 g, 0.28 mmol) in toluene (15 mL). The resultingreaction mixture was stirred at ambient temperature overnight and at50-60° C. for 5 h. The volatiles were evaporated in vacuo and theresidue was subjected to flash column chromatography over silica gel(230-400 mesh) to afford the title compound as a white solid (0.073 g,62%).

¹H NMR (300 MHz, CDCl₃): δ 7.93 (d, 2H, J=9.0 Hz), 7.39 (d, 2H, J=9.0Hz), 7.06 (d, 1H, J=2.4 Hz), 6.62 (br s, 1H), 6.53 (d, 1H, J=2.4 Hz),3.88 (s, 3H), 2.05-1.97 (m, 1H), 1.89 (s, 2H), 1.35 (s, 6H), 1.01-0.97(m, 2H), 0.90-0.83 (m, 2H), 0.67-0.54 (m, 4H).

4-{3-[8-Cyclopropyl-3,3-dihydro-4,4-dimethylspiro(2H-1-benzopyran-2,2′-cyclopropane)-6-yl]-ureido}-benzoicacid Compound 5

A solution of4-{3-[8-cyclopropyl-3,3-dihydro-4,4-dimethylspiro(2H-1-benzopyran-2,2′-cyclopropane)-6-yl]-ureido}-benzoicacid methyl ester (Intermediate 6, 0.072 g, 0.17 mmol) in methanol (3.4mL) and tetrahydrofuran (7 mL) was treated with a 0.5M solution ofsodium hydroxide (3.4 mL, 1.7 mmol) and the resulting reaction mixturewas stirred at ambient temperature overnight. The volatiles wereevaporated in vacuo to a residue that was diluted with water,neutralized with 10% hydrochloric acid and extracted with ethyl acetate.The organic phase was dried over anhydrous magnesium sulfate, filteredand evaporated in vacuo to afford the title product as a white solid(0.066 g, 95%).

¹H NMR (300 MHz, CD₃COCD₃): δ 8.27 (br s, 1H), 7.82 (d, 2H, J=9.0 Hz),7.52 (d, 2H, J=9.0 Hz), 7.20 (d, 1H, J=2.4 Hz), 6.66 (d, 1H, J=2.4 Hz),1.93-1.90 (m, 1H), 1.80 (s, 2H), 1.24 (s, 6H), 0.80-0.73 (m, 2H),0.72-0.67 (m, 2H), 0.57-0.41 (m, 4H).

General Procedure C6-Bromo-8-[(cyclopropyl-amino)-methyl]-2,2,4,4-tetramethyl-chromanIntermediate 7

A stirred, cooled (ice bath) solution of 6-bromo-2,2,4,4-tetramethylchroman-8-carbaldehyde (U.S. Pat. No. 6,252,090, 2.4 g, 8.4 mmol) indichloromethane (10 mL) and acetonitrile (9 mL) was treated withcyclopropyl amine (1.45 mL, 21 mmol). After 5 minutes, acetic acid (1mL) was added followed by sodium cyanoborohydride (1.33 g, 21 mmol). Thereaction mixture was stirred at ambient temperature for 2 h. Thevolatiles were distilled off in vacuo, the residue was diluted withwater and extracted with ethyl acetate (×2). The combined organicextract was washed with water, saturated aqueous sodium bicarbonate andbrine, dried over anhydrous sodium sulfate, filtered and evaporated invacuo to an oil. Flash column chromatography over silica gel (230-400mesh) afforded the title compound (1.4 g, 50%) as a clear oil.

¹H NMR (300 MHz, CDCl₃): δ 7.27 (d, 1H, J=2.1 Hz), 7.16 (d, 1H, J=2.1Hz), 3.73 (s, 2H), 2.19 (br s, 1H), 2.09-2.04 (m, 1H), 1.82 (s, 2H),1.35 (s, 6H), 1.32 (s, 6H), 0.43-0.36 (m, 4H).

6-Bromo-8-[(cyclopropyl-formyl-amino)-methyl]-2,2,4,4-tetramethyl-chromanIntermediate 8

A solution of6-bromo-8-[(cyclopropyl-amino)-methyl]-2,2,4,4-tetramethyl-chroman(Intermediate 7, 1.4 g, 4.14 mmol) in ethyl formate was refluxed for 6h. The solvent was distilled off in vacuo to afford the title compoundas a clear oil (1.56 g, 100%).

¹H NMR (300 MHz, CDCl₃): δ 8.37, 8.27 (2s, 1H), 7.35, 7.29 (2d, 1H,J=2.1 Hz), 7.13, 7.11 (2d, 1H, J=2.1 Hz), 4.48 (s, 2H), 2.60-2.50 (m,1H), 1.81 (s, 2H), 1.34 (s, 6H), 1.32 (s, 6H), 0.74-0.70 (m, 4H).

6-Bromo-8-[(cyclopropyl-methyl-amino)-methyl]-2,2,4,4-tetramethyl-chromanIntermediate 9

A solution of6-bromo-8-[(cyclopropyl-formyl-amino)-methyl]-2,2,4,4-tetramethyl-chroman(Intermediate 8, 1.46 g, 4.0 mmol) in anhydrous tetrahydrofuran (30 mL)was treated with a 2M solution of borane:methylsulfide complex intetrahydrofuran (5 mL, 10 mmol) and the resulting reaction mixture wasrefluxed for 2 h. It was then cooled in an ice bath, quenched cautiouslywith saturated aqueous sodium carbonate solution and extracted withdiethyl ether. The organic phase was washed with water and brine, driedover anhydrous magnesium sulfate, filtered and evaporated in vacuo toafford the title product as a white solid (1.55 g, 100%).

¹H NMR (300 MHz, CDCl₃): δ 7.26 (d, 1H, J=2.1 Hz), 7.20 (d, 1H, J=2.1Hz), 3.64 (s, 2H), 2.27 (s, 3H), 1.83 (s, 2H), 1.83-1.78 (m, 1H), 1.34(s, 6H), 1.33 (s, 6H), 0.48-0.47 (m, 4H).

General Procedure D8-[(Cyclopropyl-methyl-amino)-methyl]-2,2,4,4-tetramethyl-6-trimethylsilanylethynylchroman Intermediate 10

A solution of6-bromo-8-[(cyclopropyl-formyl-amino)-methyl]-2,2,4,4-tetramethyl-chroman(Intermediate 9, 1.5 g, 4.2 mmol) in triethyl amine (5 mL) and anhydroustetrahydrofuran (10 mL) was treated with copper(I)iodide (0.32 g, 1.68mmol) and sparged with argon for 5 minutes. Trimethylsilyl acetylene(2.5 mL, 17.6 mmol) was then added followed bydichlorobis(triphenylphosphine)palladium(II) (0.737 g, 1.05 mmol). Theresulting reaction mixture was heated at 70° C. for 17 h. It was thencooled to ambient temperature, diluted with diethyl ether and filteredover a bed of celite. The filtrate was evaporated vacuo to an oil whichwas subjected to flash column chromatography over silica gel (230-400mesh) to afford the title compound as a brown oil.

¹H NMR (300 MHz, CDCl₃): δ 7.08 (d, 1H, J=2.1 Hz), 6.97 (d, 1H, J=2.1Hz), 3.40 (s, 2H), 2.03 (s, 3H), 1.57 (s, 2H), 1.57-1.53 (m, 1H), 1.09(2s, 12H), 0.25-0.22 (m, 4H), 0.012 (s, 9H).

General Procedure F8-[(Cyclopropyl-methyl-amino)-methyl]-6-ethynyl-2,2,4,4-tetramethyl-chromanIntermediate 11

A solution of8-[(cyclopropyl-methyl-amino)-methyl]-2,2,4,4-tetramethyl-6-trimethylsilanylethynylchroman (Intermediate 10, 0.729 g, 1.97 mmol) in methanol (30 mL) wastreated with potassium carbonate (1.4 g, 10.2 mmol) and the resultingreaction mixture was stirred at ambient temperature overnight. Thesolvent was evaporated in vacuo, the residue was diluted with water andextracted with ethyl acetate. The organic phase dried over anhydrousmagnesium sulfate, filtered and evaporated in vacuo to afford the titlecompound as a brown oil (0.571 g, 98%).

¹H NMR (300 MHz, CDCl₃): δ 7.35 (d, 1H, J=2.1 Hz), 7.25 (d, 1H, J=2.1Hz), 3.66 (s, 2H), 2.98 (s, 1H), 2.28 (s, 3H), 1.83 (s, 2H), 1.83-1.77(m, 1H), 1.35 (s, 6H), 1.34 (s, 6H), 0.50-0.47 (m, 41-1).

(4-{8-[(Cyclopropyl-methyl-amino)-methyl]-2,2,4,4-tetramethyl-chroman-6-ylethynyl}phenyl)-aceticacid methyl ester Intermediate 12

Following General Procedure B and using8-[(cyclopropyl-methyl-amino)methyl]-6-ethynyl-2,2,4,4-tetramethyl-chroman(Intermediate 11, 0.09 g, 0.3 mmol), 4-iodo phenyl acetic acid methylester (U.S. Pat. No. 6,252,090, 0.092 g, 0.33 mmol), triethyl amine (3mL), copper(I)iodide (0.029 g, 0.15 mmol) anddichlorobis(triphenylphosphine)palladium(II) (0.064 g, 0.09 mmol)followed by flash column chromatography over silica gel (230-400 mesh),the title compound was obtained as a yellow oil (0.085 g, 65%).

¹H NMR (300 MHz, CDCl₃): δ 7.46 (d, 2H, J=8.4 Hz), 7.37 (d, 1H, J=2.1Hz), 7.27-7.22 (m, 3H), 3.70 (s, 3H), 3.67 (s, 2H), 3.63 (s, 2H), 2.29(s, 3H), 1.83 (s, 2H), 1.83-1.81 (m, 1H), 1.35 (2s, 12H), 0.50-0.47 (m,4H).

(4-{8-[(Cyclopropyl-methyl-amino)-methyl]-2,2,4,4-tetramethyl-chroman-6-ylethynyl}phenyl)-aceticacid Compound 6

A solution of(4-{8-[(cyclopropyl-methyl-amino)-methyl]-2,2,4,4-tetramethyl-chroman-6-ylethynyl}phenyl)-aceticacid methyl ester (Intermediate 12, 0.057 g, 0.13 mmol) in methanol (1mL) and tetrahydrofuran (3 mL) was treated with a 1M solution of sodiumhydroxide (0.4 mL, 0.4 mmol) and the resulting reaction mixture wasstirred at ambient temperature overnight. The volatiles were evaporatedin vacuo to a residue that was washed with hexane, neutralized withsaturated aqueous ammonium chloride solution and extracted with ethylacetate. The organic phase was washed with water and brine, and driedover anhydrous magnesium sulfate, filtered and evaporated in vacuo toafford the title product as a yellow oil (0.046 g, 84%).

¹H NMR (300 MHz, CDCl₃): δ 7.42-7.26 (m, 6H), 3.94 (s, 2H), 3.57 (s,2H), 2.48 (s, 3H), 2.04 (m, 1H), 1.82 (s, 2H), 1.35 (s, 6H), 1.33 (s,6H), 0.55-0.50 (m, 4H).

(4-{8-[(Cyclopropyl-methyl-amino)-methyl]-2,2,4,4-tetramethyl-chroman-6-ylethynyl}-2-fluoro-phenyl)-aceticacid methyl ester Intermediate 13

Following General Procedure B and using8-[(cyclopropyl-methyl-amino)-methyl]-6-ethynyl-2,2,4,4-tetramethyl-chroman(Intermediate 11, 0.084 g, 0.28 mmol), 2-fluoro-4-iodo phenyl aceticacid methyl ester (U.S. Pat. No. 6,252,090, 0.091 g, 0.3 mmol), triethylamine (3 mL), copper(I)iodide (0.027 g, 0.14 mmol) anddichlorobis(triphenylphosphine)palladium(II) (0.060 g, 0.085 mmol)followed by flash column chromatography over silica gel (230-400 mesh),the title compound was obtained as a yellow oil (0.083 g, 64%).

¹H NMR (300 MHz, CDCl₃): δ 7.37 (d, 1H, J=2.1 Hz), 7.27-7.24 (m, 4H),3.72 (s, 3H), 3.67 (s, 4H), 2.29 (s, 3H), 1.83 (s, 2H), 1.83-1.81 (m,1H), 1.35 (s, 12H), 0.50-0.47 (m, 4H).

(4-{8-[(Cyclopropyl-methyl-amino)-methyl]-2,2,4,4-tetramethyl-chroman-6-ylethynyl}-2-fluoro-phenyl)-aceticacid Compound 7

A solution of(4-{8-[(cyclopropyl-methyl-amino)-methyl]-2,2,4,4-tetramethyl-chroman-6-ylethynyl}-2-fluoro-phenyl)-aceticacid methyl ester (Intermediate 13, 0.060 g, 0.13 mmol) in methanol (1mL) and tetrahydrofuran (3 mL) was treated with a 1M solution of sodiumhydroxide (0.4 mL, 0.4 mmol) and the resulting reaction mixture wasstirred at ambient temperature overnight. The volatiles were evaporatedin vacuo to a residue that was washed with hexane, neutralized withsaturated aqueous ammonium chloride solution and extracted with ethylacetate. The organic phase was washed with water and brine, and driedover anhydrous magnesium sulfate, filtered and evaporated in vacuo toafford the title product as a yellow oil (0.056 g, 95%).

¹H NMR (300 MHz, CDCl₃): δ 7.43 (d, 1H, J=2.1 Hz), 7.37-7.13 (m, 4H),3.99 (s, 2H), 3.61 (s, 2H), 2.52 (s, 3H), 2.10-2.04 (m, 1H), 1.83 (s,2H), 1.83-1.81 (m, 1H), 1.36 (s, 6H), 1.35 (s, 6H), 0.90-0.82 (m, 2H),0.59-0.57 (m, 2H).

2-(4-{8-[(Cyclopropyl-methyl-amino)-methyl]-2,2,4,4-tetramethyl-chroman-6-ylethynyl}-phenyl)-propionicacid methyl ester Intermediate 14

Following General Procedure B and using8-[(cyclopropyl-methyl-amino)methyl]-6-ethynyl-2,2,4,4-tetramethyl-chroman(Intermediate 11, 0.08 g, 0.27 mmol), methyl-2-(4-iodophenyl)propionate(Reagent 1, 0.086 g, 0.29 mmol), triethyl amine (3 mL), copper(I)iodide(0.026 g, 0.14 mmol) and dichlorobis(triphenylphosphine)palladium(II)(0.057 g, 0.08 mmol) followed by flash column chromatography over silicagel (230-400 mesh), the title compound was obtained as a brown oil(0.067 g, 54%).

¹H NMR (300 MHz, CDCl₃): δ 7.46 (d, 2H, J=8.4 Hz), 7.37 (d, 1H, J=2.1Hz), 7.27-7.22 (m, 3H), 3.72 (q, 1H, J=7.2 Hz), 3.67 (s, 5H), 2.29 (s,3H), 1.83 (s, 2H), 1.83-1.79 (m, 1H), 1.50 (d, 3H, J=7.2 Hz), 1.35 (s,12H), 0.50-0.47 (m, 4H).

2-(4-{8-[(Cyclopropyl-methyl-amino)-methyl]-2,2,4,4-tetramethyl-chroman-6-ylethynyl}-phenyl)-propionicacid Compound 8

A solution of2-(4-{8-[(cyclopropyl-methyl-amino)-methyl]-2,2,4,4-tetramethyl-chroman-6-ylethynyl}-phenyl)-propionicacid methyl ester (Intermediate 14, 0.057 g, 0.12 mmol) in methanol (1mL) and tetrahydrofuran (3 mL) was treated with a 1M solution of sodiumhydroxide (0.3 mL, 0.3 mmol) and the resulting reaction mixture wasstirred at ambient temperature overnight. The volatiles were evaporatedin vacuo to a residue that was washed with hexane, neutralized withsaturated aqueous ammonium chloride solution and extracted with ethylacetate. The organic phase was washed with water and brine, and driedover anhydrous magnesium sulfate, filtered and evaporated in vacuo toafford the title product as a yellow solid (0.024 g, 45%).

¹H NMR (300 MHz, CDCl₃): δ 7.38-7.23 (2m, 6H), 3.85-3.82 (m, 1H), 3.82(s, 2H), 2.39 (s, 3H), 1.94-1.85 (m, 1H), 1.80 (s, 2H), 1.41 (d, 3H,J=7.2 Hz), 1.33 (s, 12H), 0.70-0.60 (m, 2H), 0.50-0.48 (m, 2H).

2-(4-{8-[(Cyclopropyl-methyl-amino)-methyl]-2,2,4,4-tetramethyl-chroman-6-ylethynyl}-phenyl)-2-methyl-propionicacid methyl ester Intermediate 15

Following General Procedure B and using8-[(cyclopropyl-methyl-amino)-methyl]-6-ethynyl-2,2,4,4-tetramethyl-chroman(Intermediate 11, 0.08 g, 0.27 mmol),methyl-2-(4-iodophenyl)-2-methyl-propionate (Reagent 2, 0.082 g, 0.27mmol), triethyl amine (2 mL), copper(I)iodide (0.020 g, 0.1 mmol) anddichlorobis(triphenylphosphine)palladium(II) (0.07 g, 0.1 mmol) followedby flash column chromatography over silica gel (230-400 mesh) using 10%ethyl acetate in hexane as the eluent, the title compound was obtainedas a brown oil (0.040 g, 31%).

¹H NMR (300 MHz, CDCl₃): δ 7.50-7.28 (m, 6H), 3.68 (s, 3H), 3.66 (s,2H), 2.30 (s, 3H), 1.85 (s, 2H), 1.85-1.81 (m, 1H), 1.60 (s, 3H), 1.59(s, 3H), 1.37 (s, 6H), 1.36 (s, 6H), 0.50-0.47 (m, 4H).

2-(4-{8-[(cyclopropyl-methyl-amino)-methyl]-2,2,4,4-tetramethyl-chroman-6-ylethynyl}-phenyl)-2-methyl-propionicacid Compound 9

A solution of2-(4-{8-[(cyclopropyl-methyl-amino)-methyl]-2,2,4,4-tetramethyl-chroman-6-ylethynyl}-phenyl)-2-methyl-propionicacid methyl ester (Intermediate 15, 0.040 g, 0.084 mmol) in methanol(2.5 mL) and tetrahydrofuran (2.5 mL) was treated with a 2M solution ofsodium hydroxide (1 mL, 2 mmol) and the resulting reaction mixture wasrefluxed overnight. The volatiles were evaporated in vacuo to a residuethat was neutralized with saturated aqueous ammonium chloride solutionand extracted with ethyl acetate. The organic phase was washed withwater and brine, and dried over anhydrous magnesium sulfate, filteredand evaporated in vacuo to an oil. Preparative reverse phase HPLC on apartisil 10 ODS-3 column using 10% water in acetonitrile as the mobilephase afforded the title compound (0.008 g, 27%).

¹H NMR (300 MHz, CDCl₃): δ 7.46-7.32 (m, 6H), 6.90-6.50 (br s, 1H), 3.84(s, 2H), 2.41 (s, 3H), 1.97-1.92 (m, 1H), 1.83 (s, 2H), 1.55 (s, 6H),1.36 (2s, 12H), 0.73-0.68 (m, 2H), 0.52-0.46 (m, 21-1).

8-acetyl-6-bromo-2,2,4,4-tetramethyl chroman Intermediate 15A

A stirred, cooled (−78° C.) solution of 6-bromo-2,2,4,4-tetramethylchroman (1 g, 3.72 mmol) in anhydrous dichloromethane (10 mL) wastreated with aluminum chloride (0.8 g, 6.8 mmol) followed by acetylchloride (0.4 mL, 6.08 mmol). After 10 minutes, the reaction mixture wasdiluted with water and extracted with diethyl ether. The organic phasewas washed with water, and dried over anhydrous sodium sulfate, filteredand evaporated to a residue that was subjected to flash columnchromatography on silica gel (230-400 mesh) using 10% ethyl acetate inhexane as the eluent to afford the title compound as a solid (0.78 g,67%).

¹H NMR (300 MHz, CDCl₃): δ 7.64 (d, 1H, J=2.6 Hz), 7.49 (d, 1H, J=2.6Hz), 2.60 (s, 3H), 1.87 (s, 2H), 1.41 (s, 6H), 1.36 (s, 6H).

8-Acetoxy-6-bromo-2,2,4,4-tetramethyl chroman Intermediate 16

A solution of 8-acetyl-6-bromo-2,2,4,4-tetramethyl chroman (Intermediate15A, 10.3 g, 4.18 mmol) in anhydrous dichloromethane (30 mL) was treatedwith a 77% aqueous solution of 3-chloroperoxybenzoic acid (5.75 g, 33.44mmol) and the resulting reaction mixture was stirred at ambienttemperature for 24 h. The reaction mixture was then cooled in an icebath and cautiously quenched with saturated sodium thiosulfate solution.The phases were separated and the organic phase was washed withsaturated, aqueous sodium bicarbonate solution, water and brine, driedover anhydrous sodium sulfate, filtered and evaporated in vacuo toafford a residue that on flash column chromatography over silica gel(230-400 mesh) using 10% ethyl acetate in hexane as the eluent affordedthe title compound as an oil (1.3 g, 92%).

¹H NMR (300 MHz, CDCl₃): δ 7.27 (s, 1H), 7.00 (s, 1H), 2.29 (s, 3H),1.83 (s, 2H), 1.34 (s, 6H), 1.32 (s, 6H).

6-Bromo-8-hydroxy-2,2,4,4-tetramethyl chroman Intermediate 17

A solution of 8-acetoxy-6-bromo-2,2,4,4-tetramethyl chroman(Intermediate 16, 1.3 g, 3.98 mmol) in methanol was treated with sodiumcarbonate (0.8 g, 7.95 mmol) and the resulting reaction mixture wasstirred at ambient temperature overnight. The volatiles were evaporatedin vacuo, the residue was diluted with water and extracted with ethylacetate. The organic phase was dried over anhydrous magnesium sulfate,filtered and evaporated in vacuo to afford a residue that on flashcolumn chromatography over silica gel (230-400 mesh) using 10% ethylacetate in hexane as the eluent afforded the title product as an oil(0.95 g, 84%).

¹H NMR (300 MHz, CDCl₃): δ 6.91 (d, 1H), 6.88 (d, 1H), 5.67 (s, 1H),1.84 (s, 2H), 1.37 (s, 6H), 1.32 (s, 6H).

6-Bromo-8-trimethylsilanylethynyl-2,2,4,4-tetramethyl chromanIntermediate 18

Following General Procedure D and using6-bromo-8-hydroxy-2,2,4,4-tetramethyl chroman (Intermediate 17, 1.0 g,3.51 mmol), triethyl amine (5 mL), copper(I)iodide (0.066 g, 0.351mmol), trimethylsilyl acetylene (2.5 mL, 17.6 mmol) anddichlorobis(triphenylphosphine)palladium(II) (0.246 g, 0.351 mmol)followed by flash column chromatography over silica gel (230-400 mesh)using 0.5% ethyl acetate in hexane as the eluent, the title compound(1.08 g, ˜100%) was obtained as a brown oil.

¹H NMR (300 MHz, CDCl₃): δ 6.97 (d, 1H), 6.86 (d, 1H), 5.61 (s, 1H),1.84 (s, 2H), 1.37 (s, 6H), 1.33 (s, 6H), 0.24 (s, 9H).

6-Ethynyl-8-hydroxy-2,2,4,4-tetramethyl-chroman Intermediate 19

A solution of 6-bromo-8-trimethylsilanylethynyl-2,2,4,4-tetramethylchroman (Intermediate 18, 0.47 g, 1.56 mmol) in methanol (5 mL) wastreated with potassium carbonate (0.2 g, 1.45 mmol) and the resultingreaction mixture was heated at 80° C. for 3 h. The solvent wasevaporated in vacuo, the residue was diluted with water and extractedwith ethyl acetate. The organic phase dried over anhydrous magnesiumsulfate, filtered and evaporated in vacuo to afford the title compoundas a brown oil (0.35 g, 99%).

¹H NMR (300 MHz, CDCl₃): δ 6.97 (d, 1H), 6.86 (d, 1H), 5.70 (br s, 1H),2.92 (s, 1H), 1.84 (s, 2H), 1.37 (s, 6H), 1.33 (s, 61-1).

[4-(8-Hydroxy-2,2,4,4-tetramethyl-chroman-6-ylethynyl)-phenyl]-aceticacid methyl ester Intermediate 20

Following General Procedure B and using6-ethynyl-8-hydroxy-2,2,4,4-tetramethyl-chroman (Intermediate 19, 0.035g, 0.15 mmol), 4-iodo phenyl acetic acid methyl ester (0.060 g, 0.23mmol), triethyl amine (3 mL), copper(I)iodide (0.020 g, 0.1 mmol) anddichlorobis(triphenylphosphine)palladium(II) (0.07 g, 0.1 mmol) followedby flash column chromatography over silica gel (230-400 mesh), andpreparative normal phase HPLC using 10% ethyl acetate in hexane as themobile phase, the title compound was obtained (0.015 g, 25%).

¹H NMR (300 MHz, CDCl₃): δ 7.46 (d, 2H, J=8.1 Hz), 7.24 (d, 2H, J=8.1Hz), 7.03 (d, 1H, J=2.1 Hz), 6.91 (d, 1H, J=2.1 Hz), 5.72 (s, 1H), 3.69(s, 3H), 3.63 (s, 2H), 1.86 (s, 2H), 1.38 (s, 6H), 1.35 (s, 6H).

[2-Fluoro-4-(8-hydroxy-2,2,4,4-tetramethyl-chroman-6-ylethynyl)-phenyl]-aceticacid methyl ester Intermediate 21

Following General Procedure B and using6-ethynyl-8-hydroxy-2,2,4,4-tetramethyl-chroman (Intermediate 19, 0.05g, 0.22 mmol), 2-fluoro-4-iodo phenyl acetic acid methyl ester (0.096 g,0.33 mmol), triethyl amine (3 mL), copper(I)iodide (0.020 g, 0.1 mmol)and dichlorobis(triphenylphosphine)palladium(II) (0.07 g, 0.1 mmol)followed by flash column chromatography over silica gel (230-400 mesh),and preparative normal phase HPLC using 10% ethyl acetate in hexane asthe mobile phase, the title compound was obtained (0.037 g, 43%).

¹H NMR (300 MHz, CDCl₃): δ 7.27-7.18 (m, 3H), 7.03 (d, 1H, J=1.8 Hz),6.90 (d, 1H, J=1.8 Hz), 5.68 (s, 11H), 3.72 (s, 3H), 3.67 (s, 2H), 1.87(s, 2H), 1.39 (s, 6H), 1.36 (s, 6H).

[2-Fluoro-4-(8-hydroxy-2,2,4,4-tetramethyl-chroman-6-ylethynyl)-phenyl]-aceticacid Compound 10

A solution of[2-fluoro-4-(8-hydroxy-2,2,4,4-tetramethyl-chroman-6-ylethynyl)phenyl]-aceticacid methyl ester (Intermediate 21, 0.037 g, 0.0493 mmol) in methanol (2mL) and tetrahydrofuran (1 mL) was treated with a 2M solution ofpotassium hydroxide (2 mL, 4 mmol) and the resulting reaction mixturewas stirred at ambient temperature for 2 h. The volatiles wereevaporated in vacuo to a residue that was neutralized with saturatedaqueous ammonium chloride solution and extracted with ethyl acetate. Theorganic phase was washed with water and brine, and dried over anhydrousmagnesium sulfate, filtered and evaporated in vacuo to afford the titleproduct (0.024 g, 69%).

¹H NMR (300 MHz, CDCl₃): δ 7.26-7.24 (m, 3H), 7.03 (d, 1H, J=1.8 Hz),6.90 (d, 1H, J=1.8 Hz), 3.71 (s, 2H), 1.87 (s, 2H), 1.39 (s, 6H), 1.36(s, 6H).

2-[4-(8-Hydroxy-2,2,4,4-tetramethyl-chroman-6-ylethynyl)-phenyl]-propionicacid methyl ester Intermediate 22

Following general procedure B and using6-ethynyl-8-hydroxy-2,2,4,4-tetramethyl-chroman (Intermediate 19, 0.04g, 0.17 mmol), methyl-2-(4-iodophenyl)propionate (Reagent 1, 0.075 g,0.26 mmol), triethyl amine (3 mL), copper(I)iodide (0.020 g, 0.1 mmol)and dichlorobis(triphenylphosphine)palladium(II) (0.07 g, 0.1 mmol)followed by flash column chromatography over silica gel (230-400 mesh),and preparative normal phase HPLC using 5% ethyl acetate in hexane asthe mobile phase, the title compound was obtained as a brown oil (0.018g, 26%).

¹H NMR (300 MHz, CDCl₃): δ 7.46 (d, 2H, J=8.5 Hz), 7.26 (d, 2H, J=8.5Hz), 7.03 (d, 1H, J=1.8 Hz), 6.91 (d, 1H, J=1.8 Hz), 5.66 (s, 1H), 3.67(q, 1H, J=7.5 Hz), 1.87 (s, 2H), 1.50 (d, 3H, J=7.5 Hz), 1.39 (s, 6H),1.36 (s, 6H).

2-[4-(8-Hydroxy-2,2,4,4-tetramethyl-chroman-6-ylethynyl)-phenyl]-propionicacid Compound 11

A solution of2-[4-(8-hydroxy-2,2,4,4-tetramethyl-chroman-6-ylethynyl)phenyl]-propionicacid methyl ester (Intermediate 22, 0.018 g, 0.046 mmol) in methanol (1mL) and tetrahydrofuran (0.5 mL) was treated with a 2M solution ofpotassium hydroxide (1 mL, 2 mmol) and the resulting reaction mixturewas stirred at 80° C. for 2 h. The volatiles were evaporated in vacuo toa residue that was neutralized with saturated aqueous ammonium chloridesolution and extracted with ethyl acetate. The organic phase was washedwith water and brine, and dried over anhydrous magnesium sulfate,filtered and evaporated in vacuo to afford the title product as a yellowsolid (0.017 g, 100%).

¹H NMR (300 MHz, CDCl₃): δ 7.50-7.30 (m, 4H), 7.02 (s, 1H), 6.91 (s,1H), 3.80-3.70 (m, 1H), 1.86 (s, 2H), 1.52 (d, 3H, J=7.2 Hz), 1.39 (s,6H), 1.36 (s, 6H).

2-[4-(8-Hydroxy-2,2,4,4-tetramethyl-chroman-6-ylethynyl)-phenyl]-2-methyl-propionicacid methyl ester Intermediate 23

Following General Procedure B and using6-ethynyl-8-hydroxy-2,2,4,4-tetramethyl-chroman (Intermediate 19, 0.057g, 0.25 mmol), methyl-2-(4-iodophenyl)-2-methyl-propionate (Reagent 2,0.112 g, 0.37 mmol), triethyl amine (3 mL), copper(I)iodide (0.020 g,0.1 mmol) and dichlorobis(triphenylphosphine)-palladium(II) (0.07 g, 0.1mmol) followed by flash column chromatography over silica gel (230-400mesh) and preparative normal phase HPLC using 5% ethyl acetate in hexaneas the mobile phase, the title compound was obtained as a brown oil(0.035 g, 35%).

¹H NMR (300 MHz, CDCl₃): δ 7.46 (d, 2H, J=8.5 Hz), 7.29 (d, 2H, J=8.5Hz), 7.03 (d, 1H, J=1.8 Hz), 6.91 (d, 1H, J=1.8 Hz), 5.67 (s, 1H), 3.66(s, 3H), 1.86 (s, 2H), 1.58 (s, 6H), 1.39 (s, 6H), 1.36 (s, 6H).

2-[4-(8-Hydroxy-2,2,4,4-tetramethyl-chroman-6-ylethynyl)-phenyl]-2-methyl-propionicacid Compound 12

A solution of2-[4-(8-hydroxy-2,2,4,4-tetramethyl-chroman-6-ylethynyl)phenyl]-2-methyl-propionicacid methyl ester (Intermediate 23, 0.035 g, 0.087 mmol) in methanol (2mL) and tetrahydrofuran (1 mL) was treated with a 1M solution ofpotassium hydroxide (2 mL, 4 mmol) and the resulting reaction mixturewas stirred at 80° C. for 2 h. The volatiles were evaporated in vacuo toa residue that was neutralized with saturated aqueous ammonium chloridesolution and extracted with ethyl acetate. The organic phase was washedwith water and brine, and dried over anhydrous magnesium sulfate,filtered and evaporated in vacuo to afford the title product as a yellowsolid (0.034 g, 100%).

¹H NMR (300 MHz, CDCl₃): δ 7.47 (d, 2H, J=8.7 Hz), 7.35 (d, 2H, J=8.7Hz), 7.03 (d, 1H, J=1.8 Hz), 6.91 (d, 1H, J=1.8 Hz), 1.86 (s, 2H), 1.60(s, 6H), 1.39 (s, 6H), 1.36 (s, 6H).

[4-(8-Isopropoxy-2,2,4,4-tetramethyl-chroman-6-ylethynyl)-phenyl]-aceticacid methyl ester Intermediate 24

A solution of[4-(8-hydroxy-2,2,4,4-tetramethyl-chroman-6-ylethynyl)-phenyl]-aceticacid methyl ester (Intermediate 20, 0.02 g, 0.076 mmol) in acetone (2mL) was treated with potassium carbonate (0.026 g, 0.19 mmol) and2-iodopropane (5 mL, large excess) and the resulting reaction mixturewas refluxed for 30 h. The volatiles were evaporated in vacuo, theresidue was diluted with water and extracted with ethyl acetate. Theorganic phase was dried over anhydrous magnesium sulfate, filtered andevaporated in vacuo to afford the title product as an oil (0.02 g, 91%).

¹H NMR (300 MHz, CDCl₃): δ 7.47 (d, 2H, J=8.4 Hz), 7.24 (d, 2H, J=8.4Hz), 7.14 (d, 1H, J=2.1 Hz), 6.93 (d, 1H, J=2.1 Hz), 4.40 (heptet, 1H,J=6.3 Hz), 3.70 (s, 3H), 3.63 (s, 2H), 1.83 (s, 2H), 1.38 (s, 6H), 1.35(s, 6H), 1.33 (d, 3H, J=6.3 Hz).

[4-(8-Isopropoxy-2,2,4,4-tetramethyl-chroman-6-ylethynyl)-phenyl]-aceticacid Compound 13

A solution of[4-(8-isopropoxy-2,2,4,4-tetramethyl-chroman-6-ylethynyl)phenyl]-aceticacid methyl ester (Intermediate 24, 0.02 g, 0.05 mmol) in methanol (1mL) was treated with a 2M solution of sodium hydroxide (1 mL, 2 mmol)and the resulting reaction mixture was stirred at ambient temperaturefor 3 h. The volatiles were evaporated in vacuo to a residue that wasneutralized with saturated aqueous ammonium chloride solution andextracted with ethyl acetate. The organic phase was washed with waterand brine, and dried over anhydrous magnesium sulfate, filtered andevaporated in vacuo to an oil. Flash column chromatography over silicagel (230-400 mesh) using 5% methanol in ethyl acetate as the eluentfollowed by preparative reverse phase HPLC using 10% water inacetonitrile as the mobile phase afforded the title product (0.015 g,78%).

¹H NMR (300 MHz, CDCl₃): δ 7.47 (d, 2H, J=8.4 Hz), 7.24 (d, 2H, J=8.4Hz), 7.14 (d, 1H, J=2.1 Hz), 6.92 (d, 1H, J=2.1 Hz), 4.40 (heptet, 1H,J=7.5 Hz), 3.65 (s, 2H), 1.83 (s, 2H), 1.37 (s, 6H), 1.35 (s, 6H), 1.33(d, 3H, J=7.5 Hz).

6-Bromo-2,2-diethyl-4,4-dimethylchroman Intermediate 25

A solution of 6-bromo-4,4-dimethyl-chroman-2-one (U.S. Pat. No.6,252,090, 4 g, 15.7 mmol) in anhydrous tetrahydrofuran (20 mL) wastreated with a 3M solution of ethyl magnesium bromide (10.5 mL, 31.5mmol) and stirred at ambient temperature for 2 h. The reaction mixturewas poured into cold dilute hydrochloric acid and extracted with ethylacetate (×2). The combined organic extract was dried over anhydroussodium sulfate, filtered and evaporated in vacuo to afford a residuewhich was dissolved in 50 mL of benzene, treated with p-toluene sulfonicacid (1 g, 3.92 mmol) and the resulting reaction mixture was refluxedovernight. The reaction mixture cooled to ambient temperature, filteredon silica gel and washed with 10% ethyl acetate in hexane. The filtrateand washings were evaporated in vacuo to an oil which was subjected toflash column chromatography over silica gel (230-400 mesh) using 5%ethyl acetate in hexane as the eluent to afford the title compound as apale yellow oil (3.9 g, 84%).

¹H NMR (300 MHz, CDCl₃): δ 7.36 (d, 1H, J=2.4 Hz), 7.35 (dd, 1H, J=2.4,8.4 Hz), 6.70 (d, 1H, J=8.4 Hz), 1.79 (s, 2H), 1.73-1.55 (m, 4H), 1.34(s, 6H), 0.90 (t, 6H, J=7.5 Hz).

8-Acetyl-6-bromo-2,2-diethyl-4,4-dimethyl chroman Intermediate 26

A stirred, cooled (ice bath) suspension of aluminum chloride (1.1 g,8.38 mmol) in anhydrous dichloromethane (20 mL) was treated with acetylchloride (0.6 mL, 8.38 mmol). After 5 minutes, a solution of6-bromo-2,2-diethyl-4,4-dimethyl chroman (Intermediate 25, 1.66 g, 5.59mmol) in dichloromethane was added. The reaction mixture was stirred for1 h. The reaction mixture was then poured into water and extracted withdiethyl ether (×2). The combined organic phase was washed with saturatedaqueous sodium bicarbonate solution, dried over anhydrous sodiumsulfate, filtered and evaporated in vacuo to a residue which wassubjected to flash column chromatography over silica gel (230-400 mesh)using 10% ethyl acetate in hexane as the eluent to afford the titlecompound as an oil (1.6 g, 84%).

¹H NMR (300 MHz, CDCl₃): δ 7.64 (d, 1H, J=2.1 Hz), 7.48 (d, 1H, J=2.1Hz), 2.62 (s, 3H), 1.84 (s, 2H), 1.75-1.59 (m, 4H), 1.36 (s, 6H), 0.93(t, 6H, J=7.5 Hz).

6-Bromo-2,2-diethyl-8-isopropyl-4,4-dimethyl chroman Intermediate 27

A stirred, cooled (ice bath) solution of8-acetyl-6-bromo-2,2-diethyl-4,4-dimethyl chroman (Intermediate 26, 1.57g, 4.62 mmol) in anhydrous tetrahydrofuran (10 mL) was treated with a 3Msolution of methyl magnesium bromide in diethyl ether (3.1 mL, 9.24mmol). The reaction mixture was allowed to warm to ambient temperatureover 2 h. The reaction mixture was poured into cold, dilute aqueoushydrochloric acid and extracted with ethyl acetate. The organic phasewas dried over anhydrous magnesium sulfate, filtered and evaporated invacuo to a residue which on flash column chromatography over silica gel(230-400 mesh) using 5-10% ethyl acetate in hexane as the eluentafforded an oil (1.41 g, 86%). A stirred, cooled (ice bath) solution ofthe oil (1.4 g, 3.93 mmol) in dichloromethane (10 mL) was treated withtriethylsilane (5 mL, 31.46 mmol) followed after 30 minutes bytrifluoroacetic acid (2.4 mL, 31.46 mmol) and the resulting reactionmixture was allowed to warm to ambient temperature and stirred for 3 h.The volatiles were distilled off in vacuo and the residue was dilutedwith water and extracted with ethyl acetate. The combined organic phasewas dried over anhydrous sodium sulfate, filtered and evaporated invacuo to an oil which was subjected to flash column chromatography oversilica gel (230-400 mesh) to afford the title compound as a clear oil(0.89 g, 66%) and some recovered starting material (0.23 g, 16.4%).

¹H NMR (300 MHz, CDCl₃): δ 7.21 (d, 1H, J=2.1 Hz), 7.11 (d, 1H, J=2.1Hz), 3.40-3.30 (m, 1H), 1.78 (s, 2H), 1.68-1.58 (m, 4H), 1.33 (s, 6H),1.90 (d, 6H, J=6.6 Hz), 0.92 (t, 6H, J=7.5 Hz).

2,2-Diethyl-8-isopropyl-6-trimethylsilanylethynyl-4,4-dimethyl chromanIntermediate 28

Following General Procedure D and using6-bromo-2,2-diethyl-8-isopropyl-4,4-dimethyl chroman (Intermediate 27,0.89 g, 2.62 mmol), triethyl amine (5 mL), tetrahydrofuran (10 mL),copper(I)iodide (0.050 g, 0.26 mmol), trimethylsilyl acetylene (2.5 mL,17.6 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.184 g,0.26 mmol) followed by flash column chromatography over silica gel(230-400 mesh) using hexane to 2% ethyl acetate in hexane as the eluent,the title compound (0.73 g, 79%) was obtained as a brown oil.

¹H NMR (300 MHz, CDCl₃): δ 7.31 (d, 1H), 7.12 (d, 1H), 3.20-3.10 (m,1H), 1.70 (s, 2H), 1.70-1.45 (m, 4H), 1.34 (s, 6H), 0.95 (d, 6H), 0.68(t, 6H), 0.00 (s, 9H).

2,2-Diethyl-6-ethynyl-8-isopropyl-4,4-dimethyl chroman Intermediate 29

A solution of2,2-diethyl-8-isopropyl-6-trimethylsilanylethynyl-4,4-dimethyl chroman(Intermediate 28, 0.73 g, 2.04 mmol) in methanol (40 mL) was treatedwith potassium carbonate (0.15 g, 1.08 mmol) and the resulting reactionmixture was heated at 80° C. for 3 h. The solvent was evaporated invacuo, the residue was diluted with water and extracted with ethylacetate. The organic phase was dried over anhydrous magnesium sulfate,filtered and evaporated in vacuo to afford the title compound as a brownoil (0.56 g, 96%).

¹H NMR (300 MHz, CDCl₃): δ 7.27 (d, 1H), 7.16 (d, 1H), 3.31-3.06 (m,1H), 2.96 (s, 1H), 1.81 (s, 2H), 1.81-1.56 (m, 4H), 1.31 (s, 6H), 1.17(d, 6H), 0.91 (t, 6H).

2-[4-(2,2-Diethyl-8-isopropyl-4,4-dimethyl-chroman-6-ylethynyl)-phenyl]-2-methyl-propionicacid methyl ester Intermediate 30

Following General Procedure B and using2,2-diethyl-6-ethynyl-8-isopropyl-4,4-dimethyl chroman (Intermediate 29,0.069 g, 0.24 mmol), methyl-2-(4-iodophenyl)-2-methyl-propionate(Reagent 2, 0.146 g, 0.48 mmol), triethyl amine (3 mL), copper(I)iodide(0.025 g, 0.13 mmol) and dichlorobis(triphenylphosphine)palladium(II)(0.075 g, 0.107 mmol) followed by flash column chromatography oversilica gel (230-400 mesh) using 5% ethyl acetate in hexane as theeluent, the title compound was obtained as a yellow oil (0.070 g, 62%).

¹H NMR (300 MHz, CDCl₃): δ 7.47 (d, 2H, J=8.2 Hz), 7.31 (d, 2H, J=8.2Hz), 7.30 (d, 1H, J=2.1 Hz), 7.20 (d, 1H, J=2.1 Hz), 3.65 (s, 3H),3.40-3.20 (m, 1H), 1.78 (s, 2H), 1.68-1.57 (m, 4H), 1.58 (s, 6H), 1.34(s, 6H), 1.21 (d, 6H, J=7.0 Hz), 0.91 (t, 6H, J=7.3 Hz).

2-[4-(2,2-Diethyl-8-isopropyl-4,4-dimethyl-chroman-6-ylethynyl)-phenyl]-2-methyl-propionicacid Compound 14

A solution of2-[4-(2,2-diethyl-8-isopropyl-4,4-dimethyl-chroman-6-ylethynyl)-phenyl]-2-methyl-propionicacid methyl ester (Intermediate 30, 0.070 g, 0.15 mmol) in methanol (3mL) and tetrahydrofuran (0.5 mL) was treated with a 5M solution ofpotassium hydroxide (2 mL, 10 mmol) and the resulting reaction mixturewas stirred at ambient temperature for 2 days. The volatiles wereevaporated in vacuo to a residue that was neutralized with saturatedaqueous ammonium chloride solution and extracted with ethyl acetate. Theorganic phase was washed with water and brine, and dried over anhydrousmagnesium sulfate, filtered and evaporated in vacuo to afford a residuethat on preparative reverse phase HPLC using 10% water in acetonitrileas the mobile phase afforded the title product as a yellow solid (0.035g, 51%).

¹H NMR (300 MHz, CDCl₃): δ 7.48 (d, 2H, J=8.1 Hz), 7.36 (d, 2H, J=8.2Hz), 7.31 (d, 1H, J=2.1 Hz), 7.20 (d, 1H, J=2.1 Hz), 3.40-3.20 (m, 1H),1.79 (s, 2H), 1.69-1.60 (m, 4H), 1.61 (s, 6H), 1.35 (s, 6H), 1.21 (d,6H, J=7.2 Hz), 0.92 (t, 6H, J=7.5 Hz).

6-Bromo-8-isopropyl-2,2,4,4-tetramethyl-chroman Intermediate 31

A stirred, cooled (ice bath) solution of8-acetyl-6-bromo-2,2,4,4-tetramethylchroman (Intermediate 15A, 3.1 g, 10mmol) in anhydrous tetrahydrofuran (40 mL) was treated with a 3Msolution of methyl magnesium bromide in diethyl ether (11 mL, 44 mmol).The reaction mixture was allowed to warm to ambient temperatureovernight. The reaction mixture was poured into cold, dilute aqueoushydrochloric acid and extracted with ethyl acetate. The organic phasewas dried over anhydrous magnesium sulfate, filtered and evaporated invacuo to a residue which on flash column chromatography over silica gel(230-400 mesh) using 10% ethyl acetate in hexane as the eluent affordedan oil (2.85 g, 87%). The oil (1.67 g, 5.12 mmol) was cooled (ice bath)and treated with triethylsilane (10 mL, 62 mmol) followed after 30minutes by trifluoroacetic acid (5 mL, 65 mmol) and the resultingreaction mixture was allowed to warm to ambient temperature overnight.The reaction mixture was diluted with water and extracted with ethylacetate. The combined organic phase was dried over anhydrous sodiumsulfate, filtered and evaporated in vacuo to an oil which was subjectedto flash column chromatography over silica gel (230-400 mesh) to affordthe title compound as a clear oil (1 g, 63%).

¹H NMR (300 MHz, CDCl₃): δ 7.20 (d, 1H, J=2.3 Hz), 7.09 (d, 1H, J=2.3Hz), 3.25 (heptet, 1H, J=7.1 Hz), 1.79 (s, 2H), 1.33 (s, 6H), 1.31 (s,6H), 1.15 (d, 6H, J=7.1 Hz).

6-Ethynyl-8-isopropyl-2,2,4,4-tetramethyl-chroman Intermediate 32

Following General Procedure D and using6-bromo-8-isopropyl-2,2,4,4-tetramethyl chroman (Intermediate 31, 1 g,3.2 mmol), triethyl amine (10 mL), copper(I)iodide (0.04 g, 0.21 mmol),trimethylsilyl acetylene (5 mL, 35 mmol) anddichlorobis(triphenylphosphine)palladium(II) (0.12 g, 0.17 mmol)followed by flash column chromatography over silica gel (230-400 mesh),the intermediate trimethylsilylacetylene was obtained, which wasdissolved in methanol and treated with potassium carbonate and theresulting reaction mixture was stirred at ambient temperature overnight.The solvent was evaporated in vacuo, the residue was diluted with waterand extracted with ethyl acetate. The organic phase was dried overanhydrous magnesium sulfate, filtered and evaporated in vacuo to affordthe title compound as a brown oil (0.6 g, 73%). %).

¹H NMR (300 MHz, CDCl₃): δ 7.34 (d, 1H, J=2.1 Hz), 7.21 (d, 1H, J=2.1Hz), 3.50 (heptet, 1H, J=6.8 Hz), 3.00 (s, 1H), 1.85 (s, 2H), 1.38 (s,6H), 1.37 (s, 6H), 1.22 (d, 6H, J=6.8 Hz).

3-[3-(8-Isopropyl-2,2,4,4-tetramethyl-chroman-6-ylethynyl)-phenyl]-acrylicacid ethyl ester Intermediate 33

Following General Procedure B and using6-ethynyl-8-isopropyl-2,2,4,4-tetramethylchroman (Intermediate 32, 0.05g, 0.2 mmol), ethyl-3-iodo cinnamate (Reagent 6, 0.118 g, 0.39 mmol),triethyl amine (2 mL), copper(I)iodide (0.025 g, 0.13 mmol) anddichlorobis(triphenylphosphine)palladium(II) (0.075 g, 0.107 mmol)followed by flash column chromatography over silica gel (230-400 mesh),the title compound was obtained (0.058 g, 69%).

¹H NMR (300 MHz, CDCl₃): δ 7.62-7.22 (m, 6H), 7.14 (d, 1H, J=1.8 Hz),6.39 (d, 1H, J=16.1 Hz), 4.19 (q, 2H, J=7.0 Hz), 3.21 (heptet, 1H, J=6.7Hz), 1.76 (s, 2H), 1.29 (s, 12H), 1.27 (t, 3H, J=7.0 Hz). 1.13 (d, 6H,J=6.7 Hz).

3-[3-(8-Isopropyl-2,2,4,4-tetramethyl-chroman-6-ylethynyl)-phenyl]-acrylicacid Compound 15

A solution of3-[3-(8-isopropyl-2,2,4,4-tetramethyl-chroman-6-ylethynyl)phenyl]-acrylicacid ethyl ester (Intermediate 33, 0.058 g, 0.13 mmol) in ethanol (2 mL)and tetrahydrofuran (2 mL) was treated with a 5N solution of potassiumhydroxide (2 mL, 10 mmol) and the reaction mixture was stirred atambient temperature overnight. The volatiles were evaporated in vacuo,the residue was neutralized with dilute hydrochloric acid and extractedwith ethyl acetate. The organic phase was washed with water and brine,dried over anhydrous magnesium sulfate and evaporated to afford thetitle compound (0.036 g, 66%).

¹H NMR (300 MHz, CDCl₃): δ 7.69 (d, 1H, J=15.8 Hz), 7.65 (s, 1H), 7.47(d, 1H, J=7.6 Hz), 7.39 (d, 1H, J=7.9 Hz), 7.32-7.17 (m, 2H), 7.14 (d,1H, J=1.8 Hz), 6.41 (d, 1H, J=15.8 Hz), 3.21 (heptet, 1H, J=6.7 Hz),1.76 (s, 2H), 1.29 (s, 12H), 1.13 (d, 6H, J=6.7 Hz).

8-Isopropyl-2,2,4,4-tetramethyl-chroman-6-carboxylic acid Intermediate34

A stirred, cooled (−78° C.) solution of6-bromo-8-isopropyl-2,2,4,4-tetramethyl-chroman (Intermediate 31, 0.39g, 1.26 mmol) in anhydrous diethyl ether (10 mL) was treated with a 1.7Msolution of t-butyl lithium in pentane (1.48 mL, 2.516 mmol) and thereaction mixture was stirred for 20 minutes. Carbon dioxide (generatedfrom dry ice) was bubbled into the reaction mixture. The reactionmixture was then quenched with 10% aqueous hydrochloric acid andextracted with ethyl acetate. The organic phase was washed with waterand brine, dried over anhydrous sodium sulfate, filtered and evaporatedto a residue that was subjected to flash column chromatography to affordthe title compound (0.3, 86%).

¹H NMR (300 MHz, CDCl₃): δ 7.87 (d, 1H, J=2 Hz), 7.72 (d, 1H, J=2 Hz),3.21 (heptet, 1H, J=7.0 Hz), 1.78 (s, 2H), 1.39 (s, 12H), 1.14 (d, 6H,J=7.0 Hz).

8-Isopropyl-2,2,4,4-tetramethyl-chroman-6-carboxylic acid4-(2-benzyloxycarbonyl-vinyl)-phenyl ester Intermediate 35

A solution of 8-isopropyl-2,2,4,4-tetramethyl-chroman-6-carboxylic acid

(Intermediate 34, 0.05 g, 0.18 mmol) and 3-(4-hydroxy-phenyl)-acrylicacid benzyl ester (described in Journal of Natural Products, 1990, 53(4), p 821-824, Bankova V., 0.046 g, 0.18 mmol) in anhydrousdichloromethane (5 mL) was treated with 4-(dimethylamino)pyridine (0.052g, 0.27 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (0.044 g, 0.36 mmol) and the resulting reaction mixturewas stirred at ambient temperature overnight. The reaction mixture wasthen subjected to flash column chromatography using 20% ethyl acetate inhexane as the eluent to afford the title compound as a white solid(0.076 g, 83%).

¹H NMR (300 MHz, CDCl₃): δ 7.93 (d, 1H, J=2 Hz), 7.78 (d, 1H, J=2 Hz),7.66 (d, 1H, J=16.1 Hz), 7.49 (d, 2H, J=8.5 Hz), 7.35-7.25 (m, 5H), 7.15(d, 2H, J=8.5 Hz), 6.39 (d, 1H, J=16.1 Hz), 5.18 (s, 2H), 3.24 (heptet,1H, J=7.1 Hz), 1.80 (s, 2H), 1.31 (s, 12H), 1.16 (d, 6H, J=7.1 Hz).

8-Isopropyl-2,2,4,4-tetramethyl-chroman-6-carboxylic acid4-(2-carboxy-vinyl)-phenyl ester Compound 16

A suspension of 1-butyldimethyl silane (0.3 mL, 1.85 mmol),palladium(II)acetate (0.013 g, 0.06 mmol) and triethyl amine (0.03 mL,0.2 mmol) in anhydrous dichloromethane (2 mL) under argon was treatedwith a solution of 8-isopropyl-2,2,4,4-tetramethyl-chroman-6-carboxylicacid 4-(2-benzyloxycarbonyl-vinyl)-phenyl ester (Intermediate 35, 0.063g, 0.123 mmol) in dichloromethane (2 mL) and the resulting reactionmixture was stirred overnight at ambient temperature. The reactionmixture was quenched with water and extracted with diethyl ether. Theorganic extract was dried over anhydrous sodium sulfate, filtered andevaporated to a residue that was subjected to flash columnchromatography to yield an intermediate that was treated with aceticacid (1 mL) in water (0.3 mL) and tetrahydrofuran (0.3 mL) at ambienttemperature for 1 h. The reaction mixture was diluted with water andextracted with ethyl acetate. The organic extract was dried overanhydrous sodium sulfate, filtered and evaporated to a residue that wassubjected to preparative reverse phase HPLC using 10% water inacetonitrile as the mobile phase to afford the title compound (0.007 g).

¹H NMR (300 MHz, CDCl₃): δ 7.89 (d, 1H, J=2 Hz), 7.74 (d, 1H, J=2 Hz),7.67 (d, 1H, J=15.8 Hz), 7.49 (d, 2H, J=8.8 Hz), 7.15 (d, 2H, J=8.8 Hz),6.32 (d, 1H, J=15.8 Hz), 3.20 (heptet, 1H, J=6.8 Hz), 1.77 (s, 2H), 1.29(s, 6H), 1.28 (s, 6H), 1.12 (d, 6H, J=6.8 Hz).

Ethyl-2,2,4,4-tetramethyl chroman-6-carboxylate Intermediate 36

A solution of 6-bromo-2,2,4,4-tetramethylchroman (U.S. Pat. No.6,252,090, 2.2 g, 8.08 mmol), palladium acetate (0.145 g, 0.65 mmol) and1,3-bis(diphenylphosphino)propane (0.267 g, 0.65 mmol) in a mixture ofN,N-dimethylformamide (25 mL), ethanol (20 mL) and triethyl amine (7 mL)was heated at 90° C. under an atmosphere of carbon monoxide overnight.The volatiles were distilled off in vacuo and the residue was dilutedwith water and extracted with ethyl acetate. The combined organicextract was washed with brine (×1), dried over anhydrous magnesiumsulfate, filtered and evaporated in vacuo to an oil which was subjectedto flash column chromatography over silica gel (230-400 mesh) using5-10% ethyl acetate in hexane as the eluent to afford the title compound(1.9 g, 90%).

¹H NMR (300 MHz, CDCl₃): δ 8.00 (d, 1H, J=2.3 Hz), 7.76 (dd, 1H, J=2.1,8.5 Hz), 6.79 (d, 1H, J=8.5 Hz), 4.33 (q, 2H, J=7.1 Hz), 1.85 (s, 2H),1.36 (s, 6H), 1.37 (s, 6H), 1.39-1.33 (m, 3H).

8-Formyl-2,2,4,4-tetramethyl-chroman-6-carboxylic acid ethyl esterIntermediate 37

A stirred, cooled (ice bath) solution of2,2,4,4-tetramethyl-chroman-6-carboxylic acid ethyl ester (Intermediate36, 0.5 g, 1.92 mmol) in anhydrous dichloromethane (10 mL) was treatedwith titanium tetrachloride (0.4 mL, 3.26 mmol) followed by∀,∀-dichloromethyl ether (0.17 mL, 1.92 mmol). The reaction was allowedto warm to ambient temperature over 2 days, quenched cautiously with iceand water and extracted with dichloromethane. The organic extract waswashed with water and brine, dried over sodium sulfate, filtered andevaporated in vacuo to a residue that was subjected to flash columnchromatography to afford the title compound (0.11 g, 20%).

¹H NMR (300 MHz, CDCl₃): δ 10.46 (s, 1H), 8.33 (d, 1H, J=2 Hz), 8.20 (d,1H, J=21-Hz), 4.36 (q, 2H, J=6.7 Hz), 1.93 (s, 2H), 1.45 (s, 6H), 1.42(s, 6H), 1.39 (t, 3H, J=6.7 Hz).

8-[(Cyclopropyl-isopropyl-amino)-methyl]-2,2,4,4-tetramethyl-chroman-6-carboxylicacid ethyl ester Intermediate 38

Following General Procedure C and using8-formyl-2,2,4,4-tetramethylchroman-6-carboxylic acid ethyl ester(Intermediate 37, 0.11 g, 0.23 mmol) in dichloromethane (4 mL) andacetonitrile (2 mL), cyclopropyl amine (0.08 mL, 1.1 mmol), acetic acid(0.8 mL) and sodium cyanoborohydride (0.072 g, 1.1 mmol) followed bywork up and flash column chromatography afforded an intermediate. Theintermediate (0.122 g, 0.22 mmol) was dissolved in acetone (10 mL) andtreated with potassium carbonate (0.153 g, 1.1 mmol) and isopropyliodide (0.04 mL). The resulting reaction mixture was at 60° C. for 4 h.The volatiles were evaporated in vacuo, the residue was diluted withwater and extracted with ethyl acetate. The combined organic phase wasdried over anhydrous magnesium sulfate, filtered and evaporated to anoil. Flash column chromatography over silica gel (230-400 mesh) using15-20% ethyl acetate in hexane as the eluent afforded the title compound(0.09 g, 71%) as a clear oil.

¹H NMR (300 MHz, CDCl₃): δ 7.87 (d, 1H, J=2.1 Hz), 7.85 (d, 1H, J=2.1Hz), 4.35 (q, 2H, J=7.0 Hz), 3.72 (s, 2H), 2.97 (heptet, 1H, J=6.7 Hz),1.97 (m, 1H), 1.83 (s, 2H), 1.37 (t, 3H, J=7.0 Hz), 1.37 (s, 6H), 1.35(s, 6H), 1.08 (d, 6H, J=6.7 Hz), 0.38-0.30 (m, 4H).

8-[(Cyclopropyl-isopropyl-amino)-methyl]-2,2,4,4-tetramethyl-chroman-6-carboxylicacid Intermediate 39

A solution of8-[(cyclopropyl-isopropyl-amino)-methyl]-2,2,4,4-tetramethyl-chroman-6-carboxylicacid ethyl ester (Intermediate 38, 0.09 g, 0.26 mmol) in ethanol (3 mL)and tetrahydrofuran (1 mL) was treated with a 1M solution of sodiumhydroxide (3 mL, 3 mmol) and the resulting reaction mixture was stirredat ambient temperature overnight. The volatiles were evaporated invacuo, the residue was neutralized with dilute hydrochloric acid andextracted with ethyl acetate. The organic extract was washed with waterand brine and dried over anhydrous sodium sulfate, filtered andevaporated to afford the title compound (0.079 g, 96%). It was used assuch for the next step.

8-[(Cyclopropyl-isopropyl-amino)-methyl]-2,2,4,4-tetramethyl-chroman-6-carboxylicacid 4-benzyloxycarbonylmethyl-phenyl ester Intermediate 40

A solution of8-[(cyclopropyl-isopropyl-amino)-methyl]-2,2,4,4-tetramethyl-chroman-6-carboxylicacid (Intermediate 39, 0.079 g, 0.25 mmol) and benzyl-4-hydroxy-phenylacetate (APIN, 0.06 g, 0.25 mmol) in anhydrous dichloromethane (5 mL)was treated with 4-(dimethylamino)pyridine (0.06 g, 0.5 mmol) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.072 g,0.37 mmol) and the resulting reaction mixture was stirred at ambienttemperature overnight. The reaction mixture was then subjected to flashcolumn chromatography using 20% ethyl acetate in hexane as the eluent toafford the title compound as an oil (0.093 g, 69%).

¹H NMR (300 MHz, CDCl₃): δ 7.98 (s, 2H), 7.32-7.21 (m, 7H), 7.13 (d, 2H,J=8.5 Hz), 5.11 (s, 2H), 3.73 (s, 2H), 3.66 (s, 2H), 2.93 (heptet, 1H,J=6.5 Hz), 1.93 (m, 1H), 1.84 (s, 2H), 1.07 (s, 12H), 1.07 (d, 6H,0.1=6.5 Hz).

8-[(Cyclopropyl-isopropyl-amino)-methyl]-2,2,4,4-tetramethyl-chroman-6-carboxylicacid 4-carboxymethyl-phenyl ester Compound 17

A solution of8-[(cyclopropyl-isopropyl-amino)-methyl]-2,2,4,4-tetramethyl-chroman-6-carboxylicacid 4-benzyloxycarbonylmethyl-phenyl ester (Intermediate 40, 0.093 g,0.17 mmol) in ethyl acetate (3 mL) was treated with a slurry of 10%palladium on carbon (20 mg) in ethyl acetate and the resulting reactionmixture was stirred under an atmosphere of hydrogen at ambienttemperature for 2 h. The reaction mixture was filtered over a bed ofcelite and the filtrate was evaporated to a residue that was purified byflash column chromatography over silica gel to afford the titlecompound.

6-Bromo-2,2,4,4-tetramethylchroman-8-carboxylic acid Intermediate 41

A stirred, cooled (ice bath) solution of6-bromo-2,2,4,4-tetramethylchroman-6-carbaldehyde (U.S. Pat. No.6,303,785 incorporated herein by reference; 3.31 g, 11.15 mmol) in2-methyl-2-propanol (30 mL) was treated with glacial acetic acid (30 mL)followed by 2-methyl-2-butene (12 mL, 111.5 mmol). A solution of sodiumchlorite (2.15 g, 18.95 mmol) in water (15 mL) was added dropwise to thereaction mixture. The reaction mixture was then allowed to graduallywarm up to ambient temperature and stirred for 4 h at the end of whichit was made basic 2N sodium hydroxide solution and then acidified with2N hydrochloric acid and extracted with ethyl acetate. The organic phasewas washed with brine, dried over anhydrous magnesium sulfate, filteredand evaporated in vacuo to afford the title product as a yellow solid(3.23 g, 93%).

¹H NMR (300 MHz, CDCl₃): δ 8.14 (d, 1H, J=2.7 Hz), 7.60 (d, 1H, J=2.7Hz), 1.95 (s, 2H), 1.50 (s, 6H), 1.39 (s, 6H).

6-Bromo-2,2,4,4-tetramethylchroman-8-carboxylic acid isopropyl esterIntermediate 42

A solution of 6-bromo-2,2,4,4-tetramethylchroman-8-carboxylic acid

(Intermediate 41, 0.3 g, 0.96 mmol) in anhydrous dichloromethane (15 mL)was treated with thionyl chloride (0.7 mL, 9.6 mmol) and the reactionmixture was refluxed for 18 h. It was then cooled to ambienttemperature, the volatiles were distilled off in vacuo and the residuewas dissolved in isopropanol (15 mL). 4-(Dimethylamino)pyridine (0.35 g,9.6 mmol) was added and the reaction mixture was stirred at ambienttemperature for 5 h. It was diluted with ethyl acetate and washed with2N hydrochloric acid (×2), 2N sodium hydroxide (×2), and brine, driedover anhydrous magnesium sulfate, filtered and evaporated in vacuo toafford the title product as a brown oil (0.32 g, 93%).

¹H NMR (300 MHz, CDCl₃): δ 7.60 (d, 1H, J=2.4 Hz), 7.45 (d, 1H, J=2.4Hz), 5.23 (heptet, 1H, J=6.0 Hz), 1.84 (s, 2H), 1.37 (s, 6H), 1.36 (s,6H), 1.33 (d, 6H, J=6.0 Hz).

2,2,4,4-Tetramethyl-6-trimethylsilanylethynylchroman-8-carboxylic acidisopropyl ester Intermediate 43

Following General Procedure D and using6-bromo-2,2,4,4-tetramethylchroman-8-carboxylic acid isopropyl ester(Intermediate 42, 0.32 g, 0.89 mmol), triethyl amine (2 mL),copper(I)iodide (0.060 g, 0.33 mmol), trimethylsilyl acetylene (0.5 mL,3.56 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.16 g,0.22 mmol) followed by flash column chromatography over silica gel(230-400 mesh) using 20% ethyl acetate in hexane as the eluent, thetitle compound (0.23 g, 69%) was obtained as a yellow oil.

¹H NMR (300 MHz, CDCl₃): δ 7.58 (d, 1H, J=2.4 Hz), 7.44 (d, 1H, J=2.4Hz), 5.18 (heptet, 1H, J=6.3 Hz), 1.80 (s, 2H), 1.32 (s, 6H), 1.31 (s,6H), 1.29 (d, 6H, J=6.3 Hz), 0.00 (s, 9H).

6-Ethynyl-2,2,4,4-tetramethylchroman-8-carboxylic acid isopropyl esterIntermediate 44

A solution of2,2,4,4-tetramethyl-6-trimethylsilanylethynylchroman-8-carboxylic acidisopropyl ester (Intermediate 43, 0.23 g, 0.62 mmol) in methanol (5 mL)was treated with potassium carbonate (0.85 g, 6.2 mmol) and theresulting reaction mixture was stirred at ambient temperature overnight.The solvent was evaporated in vacuo, the residue was diluted with waterand extracted with diethyl ether. The organic phase was washed withbrine, dried over anhydrous magnesium sulfate, filtered and evaporatedin vacuo to a brown oil that was subjected to flash columnchromatography over silica gel (230-400 mesh) using 20% ethyl acetate inhexane as the eluent to afford the title compound (0.0246 g, 13%).

¹H NMR (300 MHz, CDCl₃): δ 7.66 (d, 1H, J=2.1 Hz), 7.53 (d, 1H, J=2.1Hz), 5.25 (heptet, 1H, J=6.3 Hz), 3.02 (s, 1H), 1.88 (s, 2H), 1.40 (s,6H), 1.37 (d, 6H, J=6.3 Hz), 1.36 (s, 6H).

6-(4-Methoxycarbonylmethyl-phenylethynyl)-2,2,4,4-tetramethyl-chroman-8-carboxylicacid isopropyl ester Intermediate 45

Following General Procedure B and using6-ethynyl-2,2,4,4-tetramethylchroman-8-carboxylic acid isopropyl ester(Intermediate 44 0.025 g, 0.08 mmol), 4-iodo phenyl acetic acid methylester (0.027 g, 0.1 mmol), triethyl amine (2 mL), copper(I)iodide (0.008g, 0.04 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.017 g,0.024 mmol) followed by flash column chromatography over silica gel(230-400 mesh) using 40% ethyl acetate in hexane as the eluent, thetitle compound was obtained as a yellow oil (0.019 g, 53%).

¹H NMR (300 MHz, CDCl₃): δ 7.68 (d, 1H, J=2.1 Hz), 7.55 (d, 1H, J=2.1Hz), 7.49-7.24 (m, 4H), 5.25 (m, 1H), 3.70 (s, 3H), 3.64 (s, 2H), 1.88(s, 2H), 1.39 (s, 6H), 1.37 (s, 6H), 1.39-1.35 (d, 6H).

6-(4-Carboxymethyl-phenylethynyl)-2,2,4,4-tetramethyl-chroman-8-carboxylicacid isopropyl ester Compound 18

A solution of6-(4-methoxycarbonylmethyl-phenylethynyl)-2,2,4,4-tetramethyl-chroman-8-carboxylicacid isopropyl ester (Intermediate 45, 0.019 g, 0.043 mmol) in ethanol(0.3 mL), tetrahydrofuran (0.3 mL) and water (0.3 mL) was treated with1N lithium hydroxide (0.086 mL, 0.086 mmol) and the resulting reactionmixture was stirred at ambient temperature for 30 minutes. The volatileswere evaporated in vacuo to a residue that was washed with hexane:ethylacetate (3:1), neutralized with 2N hydrochloric acid and extracted withethyl acetate. The organic phase was washed with water and brine, anddried over anhydrous magnesium sulfate, filtered and evaporated in vacuoto afford the title product as a brown oil (0.015 g, 80%). ¹H NMR (300MHz, CDCl₃): δ 7.69 (d, 1H, J=2.4 Hz), 7.55 (d, 1H, J=2.4 Hz), 7.50-7.26(m, 4H), 5.25 (heptet, 1H), 3.67 (s, 2H), 1.88 (s, 2H), 1.39 (s, 6H),1.37 (s, 6H), 1.39-1.35 (d, 6H).

6-Bromo-2,2,4,4-tetramethylchroman-8-carboxylic acid 2,2-dimethylpropylester Intermediate 46

A stirred cooled (ice bath) solution of6-bromo-2,2,4,4-tetramethylchroman-8-carboxylic acid (Intermediate 41,0.5 g, 1.6 mmol), neopentylalcohol (0.35 mL, 3.2 mmol) and4-(dimethylamino)pyridine (0.03 g, 0.24 mmol) in anhydrousdichloromethane (5 mL) was treated with 1,3-dicyclohexylcarbodiimide(0.36 g, 1.76 mmol) and the reaction mixture was allowed to warm toambient temperature. After 2 h, the reaction mixture was filtered, thefiltrate was diluted with ethyl acetate and washed with 2N hydrochloricacid, 2N sodium hydroxide, and brine, dried over anhydrous magnesiumsulfate, filtered and evaporated in vacuo to afford the title product asa yellow solid (0.537 g, 88%).

¹H NMR (300 MHz, CDCl₃): δ 7.60 (d, 1H, J=2.4 Hz), 7.41 (d, 1H, J=2.4Hz), 3.91 (s, 2H), 1.78 (s, 2H), 1.30 (s, 6H), 1.27 (s, 6H), 0.95 (s,9H).

2,2,4,4-Tetramethyl-6-trimethylsilanylethynylchroman-8-carboxylic acid2,2-dimethylpropyl ester Intermediate 47

Following General Procedure D and using6-bromo-2,2,4,4-tetramethylchroman-8-carboxylic acid 2,2dimethylpropylester (Intermediate 46, 0.54 g, 1.4 mmol), triethyl amine (3 mL),copper(I)iodide (0.10 g, 0.52 mmol), trimethylsilyl acetylene (0.8 mL,5.6 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.25 g, 0.35mmol) followed by flash column chromatography over silica gel (230-400mesh) using 10% ethyl acetate in hexane as the eluent, the titlecompound (0.396 g, 71%) was obtained as a yellow oil.

¹H NMR (300 MHz, CDCl₃): δ 7.64 (d, 1H, J=1.8 Hz), 7.46 (d, 1H, J=1.8Hz), 3.94 (s, 2H), 1.81 (s, 2H), 1.33 (s, 6H), 1.30 (s, 6H), 0.98 (s,9H), 0.002 (s, 9H).

6-Ethynyl-2,2,4,4-tetramethylchroman-8-carboxylic acid2,2-dimethylpropyl ester Intermediate 48

A solution of2,2,4,4-tetramethyl-6-trimethylsilanylethynylchroman-8-carboxylic acid2,2-dimethylpropyl ester (Intermediate 47, 0.396 g, 1 mmol) in methanol(5 mL) was treated with potassium carbonate (1.4 g, 10 mmol) and theresulting reaction mixture was stirred at ambient temperature for 30minutes. The solvent was evaporated in vacuo, the residue was dilutedwith water and extracted with ethyl acetate. The organic phase waswashed with brine, dried over anhydrous magnesium sulfate, filtered andevaporated in vacuo to afford the title compound as a brown oil (0.227g, 70%).

¹H NMR (300 MHz, CDCl₃): δ 7.72 (d, 1H, J=1.5 Hz), 7.55 (d, 1H, J=1.5Hz), 4.00 (s, 2H), 3.02 (s, 1H), 1.88 (s, 2H), 1.40 (s, 6H), 1.36 (s,6H), 1.04 (s, 9H).

6-(4-Methoxycarbonylmethyl-phenylethynyl)-2,2,4,4-tetramethyl-chroman-8-carboxylicacid 2,2-dimethylpropyl ester Intermediate 49

Following General Procedure B and using6-ethynyl-2,2,4,4-tetramethylchroman-8-carboxylic acid2,2-dimethylpropyl ester (Intermediate 48, 0.227 g, 0.70 mmol), 4-iodophenyl acetic acid methyl ester (0.23 g, 0.83 mmol), triethyl amine (3mL), copper(I)iodide (0.07 g, 0.39 mmol) anddichlorobis(triphenylphosphine)palladium(II) (0.15 g, 0.21 mmol)followed by flash column chromatography over silica gel (230-400 mesh)using 20% ethyl acetate in hexane as the eluent, the title compound wasobtained as a yellow oil (0.198 g, 60%).

¹H NMR (300 MHz, CDCl₃): δ 7.76 (d, 1H, J=2.4 Hz), 7.58 (d, 1H, J=2.4Hz), 7.49 (d, 2H, J=8.1 Hz), 7.26 (d, 2H, J=8.1 Hz), 4.01 (s, 2H), 3.70(s, 3H), 3.64 (s, 2H), 1.88 (s, 2H), 1.40 (s, 6H), 1.38 (s, 6H), 1.05(s, 9H).

6-(4-Carboxymethyl-phenylethynyl)-2,2,4,4-tetramethyl-chroman-8-carboxylicacid 2,2-dimethylpropyl ester Compound 19

A solution of6-(4-methoxycarbonylmethyl-phenylethynyl)-2,2,4,4-tetramethyl-chroman-8-carboxylicacid 2,2-dimethylpropyl ester (Intermediate 49, 0.198 g, 0.42 mmol) inethanol (1 mL), tetrahydrofuran (1 mL) and water (1 mL) was treated with1N lithium hydroxide (1.5 mL, 1.5 mmol) and the resulting reactionmixture was stirred at ambient temperature for 30 minutes. The reactionmixture was neutralized with 2N hydrochloric acid and extracted withethyl acetate. The organic phase was washed with water and brine, anddried over anhydrous magnesium sulfate, filtered and evaporated in vacuoto afford the title product as a greenish-yellow solid (0.16 g, 84%).

¹H NMR (300 MHz, CDCl₃): δ 7.76 (d, 1H, J=2.1 Hz), 7.59 (d, 1H, J=2.1Hz), 7.50 (d, 2H, J=8.1 Hz), 7.28 (d, 2H, J=2.1 Hz), 4.02 (s, 2H), 3.67(s, 2H), 1.89 (s, 2H), 1.41 (s, 6H), 1.39 (s, 6H), 1.06 (s, 9H).

6-Bromo-2,2,4,4-tetramethylchroman-8-carboxylic acid tert-butyl esterIntermediate 50

A solution of 6-bromo-2,2,4,4-tetramethylchroman-8-carboxylic acid(Intermediate 41, 0.3 g, 0.96 mmol) and triethyl amine (0.1 g, 0.96mmol) in anhydrous tetrahydrofuran (3 mL) was treated with2,4,6-trichlorobenzoyl chloride (0.23 g, 0.96 mmol) and the reactionmixture was allowed to stir for 20 minutes. The precipitated solid wasfiltered off and the filtrate was evaporated in vacuo to afford aresidue that was dissolved in benzene (3 mL) under argon and treatedwith 4-(dimethylamino)pyridine (0.47 g, 3.84 mmol) and2-methyl-2-propanol (0.14 g, 10.92 mmol). After 18 h, the reactionmixture was diluted with ethyl acetate and washed with 2N hydrochloricacid, 2N sodium hydroxide and brine, dried over anhydrous magnesiumsulfate, filtered and evaporated in vacuo to afford a residue that wassubjected to flash column chromatography over silica gel (230-400 mesh)using 10% ethyl acetate in hexane as the eluent to afford the titleproduct as a white solid (0.14 g, 40%).

¹H NMR (300 MHz, CDCl₃): δ 7.54 (d, 1H, J=2.4 Hz), 7.43 (d, 1H, J=2.4Hz), 1.84 (s, 2H), 1.58 (s, 9H), 1.37 (s, 6H), 1.33 (s, 6H).

2,2,4,4-Tetramethyl-6-trimethylsilanylethynylchroman-8-carboxylic acidtert-butyl ester Intermediate 51

Following General Procedure D and using6-bromo-2,2,4,4-tetramethylchroman-8-carboxylic acid tert-butyl ester(Intermediate 50, 0.195 g, 0.53 mmol), triethyl amine (2 mL),copper(I)iodide (0.040 g, 0.2 mmol), trimethylsilyl acetylene (0.3 mL,2.1 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.09 g, 0.13mmol) followed by flash column chromatography over silica gel (230-400mesh) using 10% ethyl acetate in hexane as the eluent, the titlecompound (0.064 g, 32%) was obtained as a brown oil.

¹H NMR (300 MHz, CDCl₃): δ7.57 (d, 1H, J=2.1 Hz), 7.46 (d, 1H, J=2.1Hz), 1.84 (s, 2H), 1.57 (s, 9H), 1.37 (s, 6H), 1.34 (s, 6H), 0.045 (s,9H).

6-Ethynyl-2,2,4,4-tetramethylchroman-8-carboxylic acid tert-butyl esterIntermediate 52

A solution of2,2,4,4-tetramethyl-6-trimethylsilanylethynylchroman-8-carboxylic acidtert-butyl ester (Intermediate 51, 0.064 g, 0.17 mmol) in methanol (5mL) was treated with potassium carbonate (0.23 g, 1.7 mmol) and theresulting reaction mixture was stirred at ambient temperature for 30minutes. The solvent was evaporated in vacuo, the residue was dilutedwith water and extracted with ethyl acetate. The organic phase waswashed with brine, dried over anhydrous magnesium sulfate, filtered andevaporated in vacuo to afford the title compound as a brown oil (0.051g, 97%).

¹H NMR (300 MHz, CDCl₃): δ 7.52 (d, 1H, J=2.1 Hz), 7.42 (d, 1H, J=1.5Hz), 2.93 (s, 1H), 1.79 (s, 2H), 1.51 (s, 9H), 1.31 (s, 6H), 1.27 (s,6H).

6-(4-Methoxycarbonylmethyl-phenylethynyl)-2,2,4,4-tetramethyl-chroman-8-carboxylicacid tert-butyl ester Intermediate 53

Following General Procedure B and using6-ethynyl-2,2,4,4-tetramethylchroman-8-carboxylic acid tert-butyl ester(Intermediate 52, 0.051 g, 0.16 mmol), 4-iodo phenyl acetic acid methylester (0.053 g, 0.19 mmol), triethyl amine (3 mL), copper(I)iodide (0.02g, 0.1 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.03 g,0.043 mmol) followed by flash column chromatography over silica gel(230-400 mesh) using 20% ethyl acetate in hexane as the eluent, thetitle compound was obtained as a yellow oil (0.014 g, 19%).

¹H NMR (300 MHz, CDCl₃): δ 7.63 (d, 1H, J=2.1 Hz), 7.53 (d, 1H, J=2.1Hz), 7.48 (d, 2H, J₁=8.2 Hz), 7.26 (d, 2H, J=8.2 Hz), 3.72 (s, 3H), 3.65(s, 2H), 1.88 (s, 2H), 1.60 (s, 9H), 1.40 (s, 6H), 1.38 (s, 6H).

6-(4-Carboxymethyl-phenylethynyl)-2,2,4,4-tetramethyl-chroman-8-carboxylicacid tert-butyl ester Compound 20

A solution of6-(4-methoxycarbonylmethyl-phenylethynyl)-2,2,4,4-tetramethyl-chroman-8-carboxylicacid tert-butyl ester (Intermediate 53, 0.014 g, 0.03 mmol) in ethanol(0.3 mL), tetrahydrofuran (0.3 mL) and water (0.3 mL) was treated with1N lithium hydroxide (0.12 mL, 0.12 mmol) and the resulting reactionmixture was stirred at ambient temperature for 3 h. The reaction mixturewas neutralized with 2N hydrochloric acid and extracted with ethylacetate. The organic phase was washed with water and brine, and driedover anhydrous magnesium sulfate, filtered and evaporated in vacuo toafford the title product as a yellow oil (0.012 g, 88%).

¹H NMR (300 MHz, CDCl₃): δ 7.63 (d, 1H, J=2.1 Hz), 7.52 (d, 1H, J=2.1Hz), 7.47 (d, 2H, J=8.2 Hz), 7.26 (d, 2H, J=2.1 Hz), 3.67 (s, 2H), 1.87(s, 2H), 1.59 (s, 9H), 1.39 (s, 6H), 1.36 (s, 6H).

Trifluoro-methanesulfonic acid5-(cyclopropyl-methyl-amino)-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-ylester Intermediate 54

A solution of4,4-dimethyl-6-trifluoromethylsulfonyloxy-1,2,3,4-tetrahydronaphthalene-1-one(U.S. Pat. No. 6,252,090, 0.85 g, 2.64 mmol) in dichloromethane (6 mL)and acetonitrile (3 mL) was treated with cyclopropyl amine (3 mL, 43.4mmol). After 5 minutes, acetic acid (3 mL) was added followed by sodiumcyanoborohydride (0.66 g, 10.55 mmol). The reaction was stirredovernight at ambient temperature. It was then diluted with water andsaturated aqueous sodium carbonate solution and extracted with ethylacetate. The combined organic extract was washed with water and brine,dried over anhydrous sodium sulfate, filtered and evaporated in vacuo toan oil. The oil was dissolved in acetone (20 mL) and treated withpotassium carbonate (1.08 g, 7.8 mmol) and methyl iodide (1.6 mL, 26mmol). The resulting reaction mixture was stirred at ambient temperatureovernight. The solids were filtered off, the filtrate was evaporated invacuo and the residue was subjected to flash column chromatography oversilica gel (230-400 mesh) to afford the title compound (0.85 g, 87%) asa colorless oil.

¹H NMR (300 MHz, CDCl₃): δ 7.61 (d, 1H, J=9.0 Hz), 7.11 (d, 1H, J=2.4Hz), 6.97 (dd, 1H, J=2.4, 9.0 Hz), 3.92 (t, 1H, J=8.4 Hz), 2.14-2.10 (m,1H), 2.12 (s, 3H), 1.96-1.89 (m, 2H), 1.79-1.57 (m, 2H), 1.29 (s, 3H),1.25 (s, 3H), 0.52-0.36 (m, 4H).

General Procedure E5-(Cyclopropyl-methyl-amino)-8,8-dimethyl-5,6,7,8-tetrahydronaphthalene-2-carboxylicacid methyl ester Intermediate 55

A solution of trifluoro-methanesulfonic acid5-(cyclopropyl-methyl-amino)-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-ylester (Intermediate 54, 0.37 g, 0.98 mmol), palladium acetate (0.05 g,0.22 mmol) and 1,3-bis(diphenylphosphino)propane (0.096 g, 0.23 mmol) ina mixture of dimethylformamide (4 mL), methanol (4 mL) and triethylamine (2 mL) was heated at 70° C. under an atmosphere of carbon monoxideovernight. The volatiles were distilled of in vacuo and the residue wasdiluted with water and extracted with diethyl ether (×3). The combinedorganic extract was dried over anhydrous magnesium sulfate, filtered andevaporated in vacuo to an oil which was subjected to flash columnchromatography over silica gel (230-400 mesh) using 2-5% ethyl acetatein hexane as the eluent, to afford the title compound (0.236 g, 85%).

¹H NMR (300 MHz, CDCl₃): δ 7.96 (d, 1H, J=1.8 Hz), 7.73 (dd, 1H, J=1.8,8.1 Hz), 7.59 (d, 1H, J=8.1 Hz), 3.96 (t, 1H, J=7.5 Hz), 3.89 (s, 3H),2.17-2.10 (m, 1H), 2.12 (s, 3H), 1.98-1.83 (m, 2H), 1.82-1.60 (m, 2H),1.34 (s, 3H), 1.28 (s, 3H), 0.54-0.39 (m, 4H).

5-(Cyclopropyl-methyl-amino)-8,8-dimethyl-5,6,7,8-tetrahydronaphthalene-2-carboxylicacid Intermediate 56

A solution of5-(cyclopropyl-methyl-amino)-8,8-dimethyl-5,6,7,8-tetrahydronaphthalene-2-carboxylicacid methyl ester (Intermediate 55, 0.236 g, 0.83 mmol) in methanol (4mL) and tetrahydrofuran (4 mL) was treated with a 2M solution of sodiumhydroxide (4 mL, 8 mmol) and the resulting reaction mixture was stirredat ambient temperature overnight. The volatiles were evaporated in vacuoto a residue that was neutralized with saturated aqueous ammoniumchloride solution and extracted with ethyl acetate. The organic phasewas dried over anhydrous magnesium sulfate, filtered and evaporated invacuo to afford the title compound as a solid (0.22 g, 100%).

¹H NMR (300 MHz, CDCl₃): δ 7.98 (d, 1H, J=1.8 Hz), 7.72 (dd, 1H, J=1.8,8.2 Hz), 7.51 (d, 1H, J=8.2 Hz), 3.93 (t, 1H, J=7.8 Hz), 2.15-2.04 (m,1H), 2.10 (s, 3H), 1.94-1.85 (m, 2H), 1.79-1.62 (m, 2H), 1.27 (s, 3H),1.22 (s, 3H), 0.52-0.40 (m, 4H).

5-(Cyclopropyl-methyl-amino)-8,8-dimethyl-5,6,7,8-tetrahydronaphthalene-2-carboxylicacid azide Intermediate 57

A stirred, cooled (ice bath) solution of5-(cyclopropyl-methyl-amino)-8,8-dimethyl-5,6,7,8-tetrahydronaphthalene-2-carboxylicacid (Intermediate 56, 0.22 g, 0.83 mmol) in anhydrous tetrahydrofuran(4 mL) was treated with triethyl amine (0.16 mL, 1.1 mmol) followed byethyl chloroformate (0.10 mL, 1.08 mmol). After 5 h, sodium azide (0.081g, 1.24 mmol) was added and the reaction mixture was allowed to warm toambient temperature and stirred overnight. The reaction mixture wasdiluted with water and extracted with ethyl acetate. The organic phasewas washed with water and brine, dried over anhydrous sodium sulfate,filtered and evaporated in vacuo to afford the title product that wasused as such for the next reaction (0.24 g, 98%).

1-[5-(Cyclopropyl-methyl-amino)-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-yl]-3-(4-iodo-phenyl)-ureaIntermediate 58

A solution of5-(cyclopropyl-methyl-amino)-8,8-dimethyl-5,6,7,8-tetrahydronaphthalene-2-carboxylicacid azide (Intermediate 57, 0.12 g, 0.4 mmol) in anhydrous toluene (14mL) was refluxed under argon for 2 h. 4-iodoaniline (0.114 g, 0.52 mmol)was added and the solution was cooled to ambient temperature and stirredovernight. The volatiles were evaporated in vacuo and the residue wassubjected to flash column chromatography over silica gel (230-400 mesh)using 20-25% ethyl acetate in hexane as the eluent to afford the titlecompound (0.13 g, 67%).

¹H NMR (300 MHz, CDCl₃): δ 7.58 (d, 2H, J=8.7 Hz), 7.51 (d, 1H, J=8.1Hz), 7.23 (d, 1H, J=1.8 Hz), 7.14 (d, 2H, J=8.7 Hz), 6.99 (dd, 1H,J=1.8, 8.1 Hz), 6.99 (br s, 1H), 6.57 (br s, 1H), 3.92 (t, 1H, J=7.2Hz), 2.13-2.05 (m, 1H), 2.13 (s, 3H), 1.93-1.88 (m, 2H), 1.78-1.62 (m,2H), 1.29 (s, 3H), 1.26 (s, 3H), 0.52-0.39 (m, 4H).

4-{3-[5-(Cyclopropyl-methyl-amino)-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-yl]-ureido}-benzoicacid methyl ester Intermediate 59

Following General Procedure E and using1-[5-(cyclopropyl-methyl-amino)-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-yl]-3-(4-iodo-phenyl)-urea(Intermediate 58, 0.13 g, 0.267 mmol), palladium acetate (0.02 g, 0.09mmol), 1,3-bis(diphenylphosphino)propane (0.042 g, 0.101 mmol),N,N-dimethylformamide (3 mL), methanol (3 mL) and triethyl amine (1 mL)followed by flash column chromatography over silica gel (230-400 mesh)using 30-40% ethyl acetate in hexane as the eluent the title compoundwas obtained (0.045 g, 40%).

¹H NMR (300 MHz, CDCl₃): δ 7.91 (d, 2H, J=8.4 Hz), 7.51 (d, 1H, J=8.1Hz), 7.42 (s, 1H), 7.37 (d, 2H, J=8.4 Hz), 7.26 (d, 1H, J=1.8 Hz), 7.09(s, 1H), 6.97 (dd, 1H, J=2.1, 8.1 Hz), 3.89 (s, 3H), 3.90-3.84 (m, 1H),2.11-2.06 (m, 1H), 2.09 (s, 3H), 1.89-1.80 (m, 2H), 1.80-1.64 (m, 2H),1.24 (s, 3H), 1.21 (s, 3H), 0.50-0.36 (m, 4H).

4-{3-[5-(Cyclopropyl-methyl-amino)-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-yl]-ureido}-benzoicacid Compound 21

A solution of4-{3-[5-(cyclopropyl-methyl-amino)-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-yl]-ureido}-benzoicacid methyl ester (Intermediate 59, 0.045 g, 0.106 mmol) in methanol (2mL) and tetrahydrofuran (3 mL) was treated with a 2M solution of sodiumhydroxide (1 mL, 2 mmol) and the resulting reaction mixture was stirredat ambient temperature overnight. The reaction mixture was neutralizedwith 5% aqueous hydrochloric acid and extracted with ethyl acetate. Theorganic phase was washed with water and brine, and dried over anhydrousmagnesium sulfate, filtered and evaporated in vacuo to afford a solidthat was recrystallized from hot acetonitrile to afford the titleproduct as a white solid (0.012 g, 28%).

¹H NMR (300 MHz, CD₃OD): δ 7.95 (d, 2H, J=9.0 Hz), 7.53 (d, 2H, J=9.0Hz), 7.46 (d, 1H, J=2.1 Hz), 7.40 (d, 1H, J=8.7 Hz), 7.09 (s, 1H), 7.19(dd, 1H, J=2.1, 8.7 Hz), 4.06 (t, 1H, J=6.0 Hz)), 2.30-2.25 (m, 1H),2.28 (s, 3H), 2.05-1.98 (m, 2H), 1.82-1.68 (m, 2H), 1.32 (s, 3H), 1.30(s, 3H), 0.60-0.48 (m, 4H).

4-(4-Bromo-2-methoxy-phenyl)-4-oxo-butyric acid ethyl ester Intermediate60

A stirred, cooled (−30° C.) solution of 3-bromo anisole (Aldrich, 18.7g, 100 mmol) and ethyl succinyl chloride (21 mL, 150 mmol) in anhydrousdichloromethane (200 mL) was treated with aluminum chloride (26.6 g, 200mmol) and the reaction mixture was allowed to warm to ambienttemperature and stirred overnight. The reaction mixture was poured intowater and extracted with dichloromethane (×2). The combined organicphase was washed with brine, dried over anhydrous sodium sulfate,filtered and evaporated in vacuo to a brown oil. A solid separated outon standing. The supernatant liquid was decanted and the solid waswashed with 1:3 dichloromethane:hexane and dried to afford the titlecompound. The combined mother liquor and washings were evaporated to abrown oil that was subjected to flash column chromatography over silicagel (230-400 mesh) using 15% ethyl acetate in hexane as the eluent toafford the title compound (overall 12 g, 38%), and its isomer4-(2-romo-4-methoxy-phenyl)-4-oxo-butyric acid ethyl ester (11.4 g, 36%)and a 1:1 mixture of both (2 g, 6.3%).

¹H NMR (300 MHz, CDCl₃): δ 7.56 (d, 1H, J=8.7 Hz), 7.07-7.03 (m, 2H),4.07 (q, 2H, J=7.2 Hz), 3.84 (s, 3H), 3.20 (t, 2H, J=6.3 Hz), 2.61 (t,2H, J=6.3 Hz), 1.19 (t, 3H, J=7.2 Hz).

4-(4-Bromo-2-methoxy-phenyl)-butyric acid ethyl ester Intermediate 61

A solution of 4-(4-bromo-2-methoxy-phenyl)-4-oxo-butyric acid ethylester (Intermediate 60, 14.73 g, 46.8 mmol) in trifluoroacetic acid (72mL, 935 mmol) was treated with triethylsilane (30 mL, 187 mmol) and theresulting reaction mixture was heated at 55° C. for 4 h. The reactionmixture was then cooled to ambient temperature, neutralized with solidsodium bicarbonate, diluted with water and extracted with diethyl ether.The organic phase was washed with water and brine, dried over anhydrousmagnesium sulfate, filtered and evaporated in vacuo to afford a residuethat was subjected to flash column chromatography over silica gel(230-400 mesh) using 8% ethyl acetate in hexane as the eluent to affordthe title compound (7.4 g, 53%) as a colorless oil.

¹H NMR (300 MHz, CDCl₃): δ 7.02-6.94 (m, 3H), 4.11 (q, 2H, J=7.2 Hz),3.79 (s, 3H), 2.60 (t, 2H, J=7.2 Hz), 2.29 (t, 2H, J=7.2 Hz), 1.88(quintet, 2H, J=7.2 Hz), 1.25 (t, 3H, J=7.2 Hz).

5-(4-Bromo-2-methoxy-phenyl)-2-methyl-pentan-2-ol Intermediate 62

A stirred, cooled (−10° C.) solution of4-(4-bromo-2-methoxy-phenyl)-butyric acid ethyl ester (Intermediate 61,7.4 g, 24.6 mmol) in anhydrous tetrahydrofuran (50 mL) was treated witha 3M solution of methyl magnesium bromide (20.5 mL, 61.5 mmol) and theresulting reaction mixture was allowed to warm to ambient temperatureover 3 h. It was quenched with saturated, aqueous ammonium chloridesolution, diluted with water and extracted with diethyl ether. Theorganic phase was washed with water and brine, dried over anhydrousmagnesium sulfate, filtered and evaporated in vacuo to afford the titleproduct (7.3 g, 100%).

¹H NMR (300 MHz, CDCl₃): δ 6.92-6.87 (m, 3H), 3.71 (s, 3H), 2.48 (t, 2H,J=7.2 Hz), 1.55-1.38 (m, 4H), 1.11 (s, 6H).

7-Bromo-5-methoxy-1,1-dimethyl-1,2,3,4-tetrahydro-naphthaleneIntermediate 63

5-(4-Bromo-2-methoxy-phenyl)-2-methyl-pentan-2-ol (Intermediate 62, 7.3g, 24.6 mmol) was treated with 85% sulfuric acid (25 mL) at ambienttemperature. After 30 minutes, the reaction mixture was diluted withcold water and extracted with diethyl ether. The organic phase waswashed with water and brine, dried over anhydrous magnesium sulfate,filtered and evaporated in vacuo to afford the title product (5.6 g,83%).

¹H NMR (300 MHz, CDCl₃): δ 7.01 (d, 1H, J=1.8 Hz), 6.68 (d, 1H, J=1.8Hz), 3.71 (s, 3H), 2.49 (t, 2H, J=6.3 Hz), 1.71-1.65 (m, 2H), 1.55-1.51(m, 2H), 1.18 (s, 6H).

6-Bromo-8-methoxy-4,4-dimethyl-3,4-dihydro-2H-naphthalen-1-oneIntermediate 64

A solution of7-bromo-5-methoxy-1,1-dimethyl-1,2,3,4-tetrahydro-naphthalene(Intermediate 63, 5.6 g, 20.81 mmol) in glacial acetic acid (20 mL) wascooled to 0° C. and treated with a solution of chromium trioxide (6.16g, 61.6 mmol) in acetic acid and water (25 mL). The reaction mixture wasthen allowed to warm to ambient temperature and stirred for 48 h. It wasdiluted with water and extracted with diethyl ether (×2). The combinedorganic phase was washed with water (×3), saturated aqueous sodiumbicarbonate (×1) and brine (×1), dried over anhydrous magnesium sulfate,filtered and evaporated in vacuo to afford an oil. Flash columnchromatography over silica gel (230-400 mesh) using 10-20-100% ethylacetate in hexane as the eluent afforded the title compound (2 g, 33%)as a yellow oil and recovered starting material (2.2 g, 39%).

¹H NMR (300 MHz, CDCl₃): δ 7.12 (d, 1H, J=1.8 Hz), 6.97 (d, 1H, J=1.8Hz), 3.87 (s, 3H), 2.66 (t, 2H, J=6.6 Hz), 1.92 (t, 2H, J=6.6 Hz), 1.33(s, 6H).

6-Bromo-8-hydroxy-4,4-dimethyl-3,4-dihydro-2H-naphthalen-1-oneIntermediate 65

A stirred, cooled (ice bath) solution of6-bromo-8-methoxy-4,4-dimethyl-3,4-dihydro-2H-naphthalen-1-one(Intermediate 64, 0.24 g, 0.83 mmol) in anhydrous dichloromethane (4 mL)was treated with aluminum chloride (0.4 g, 3 mmol). The reaction mixturewas allowed to warm to ambient temperature and stirred overnight. It waspoured into water and extracted with dichloromethane and ethyl acetate.The combined organic phase was dried over anhydrous magnesium sulfate,filtered and evaporated in vacuo to a brown oil that was subjected toflash column chromatography over silica gel (230-400 mesh) using 10%ethyl acetate in hexane as the eluent to afford the title product as apale yellow solid (0.13 g, 56%).

¹H NMR (300 MHz, CDCl₃): δ 12.85 (s, 1H), 7.00 (d, 1H, J=1.5 Hz), 6.98(d, 1H, J=1.5 Hz), 2.74 (t, 2H, J=6.9 Hz), 1.96 (t, 2H, J=6.9 Hz), 1.36(s, 6H).

8-Hydroxy-4,4-dimethyl-6-trimethylsilanylethynyl-3,4-dihydro-2H-naphthalen-1-oneIntermediate 66

Following General Procedure D and using6-bromo-8-hydroxy-4,4-dimethyl-3,4-dihydro-2H-naphthalen-1-one(Intermediate 65, 1.56 g, 5.8 mmol), triethyl amine (20 mL),copper(I)iodide (0.088 g, 0.46 mmol), trimethylsilyl acetylene (3 mL,21.22 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.325 g,0.46 mmol) followed by flash column chromatography over silica gel(230-400 mesh) using hexane to 2-5% ethyl acetate in hexane as theeluent, the title compound (1.67 g, 100%) was obtained as an orangesolid.

¹H NMR (300 MHz, CDCl₃): δ 12.72 (s, 1H), 6.93 (d, 1H, J=1.5 Hz), 6.88(d, 1H, J=1.5 Hz), 2.74 (t, 2H, J=6.6 Hz), 1.96 (t, 2H, J=6.6 Hz), 1.36(s, 6H), 0.27 (s, 9H).

6-Ethynyl-8-hydroxy-4,4-dimethyl-3,4-dihydro-2H-naphthalen-1-oneIntermediate 67

A solution of8-hydroxy-4,4-dimethyl-6-trimethylsilanylethynyl-3,4-dihydro-2H-naphthalen-1-one(Intermediate 66, 2.2 g, 7.4 mmol) in methanol (20 mL) was treated withpotassium carbonate (2.04 g, 14.8 mmol) and the resulting reactionmixture was stirred at ambient temperature for 5 h. The solvent wasevaporated in vacuo, the residue was diluted with water and extractedwith diethyl ether. The organic phase was dried over anhydrous magnesiumsulfate, filtered and evaporated in vacuo to afford the title compoundas an oil (1.58 g, ˜100%).

¹H NMR (300 MHz, CDCl₃): δ 12.76 (s, 1H), 6.97 (d, 1H, J=1.5 Hz), 6.88(d, 1H, J=1.5 Hz), 3.28 (s, 1H), 2.73 (t, 2H, J=6.6 Hz), 1.94 (t, 2H,J=6.6 Hz), 1.34 (s, 6H).

{4-[8,8-Dimethyl-4-hydroxy-5-oxo-5,6,7,8-tetrahydro-naphthalen-2-ylethynyl]phenyl}-aceticacid methyl ester Intermediate 68

Following General Procedure B and using6-ethynyl-8-hydroxy-4,4-dimethyl-3,4-dihydro-2H-naphthalen-1-one(Intermediate 67, 1.58 g, 7.4 mmol), 4-iodo phenyl acetic acid methylester (2.2 g, 7.94 mmol), triethyl amine (12 mL), copper(I)iodide (0.38g, 1.99 mmol) and dichlorobis(triphenylphosphine)palladium(II) (1.2 g,1.71 mmol) followed by flash column chromatography over silica gel(230-400 mesh) using 16% ethyl acetate in hexane as the eluent, thetitle compound was obtained as a yellow oil (2.1 g, 78%).

¹H NMR (300 MHz, CDCl₃): δ 12.79 (s, 1H), 7.52 (d, 2H, J=8.7 Hz), 7.29(d, 2H, J=8.7 Hz), 7.01 (d, 1H, J=1.5 Hz), 6.94 (d, 1H, J=1.5 Hz), 3.71(m, 3H), 3.65 (s, 2H), 2.76 (t, 2H, J=6.6 Hz), 1.97 (t, 2H, J=6.6 Hz),1.38 (s, 6H).

{4-[8,8-Dimethyl-5-oxo-4-trifluoromethanesulfonyloxy-5,6,7,8-tetrahydro-naphthalen-2-ylethynyl]-phenyl}-aceticacid methyl ester Intermediate 69

A stirred, cooled (0° C.) solution of{4-[8,8-dimethyl-4-hydroxy-5-oxo-5,6,7,8-tetrahydro-naphthalen-2-ylethynyl]-phenyl}-aceticacid methyl ester (Intermediate 68, 2.1 g, 5.8 mmol) in anhydrousdichloromethane (20 mL) was treated with 4-(dimethylamino)pyridine (1.21g, 9.9 mmol) followed by N-phenyltrifluoromethanesulfonimide (2.2 g,6.16 mmol). After stirring at ambient temperature overnight, thereaction mixture was subjected to flash column chromatography oversilica gel (230-400 mesh) using 20% ethyl acetate in hexane as theeluent to afford the title compound (2.6 g, 91%).

¹H NMR (300 MHz, CDCl₃): δ 7.57 (d, 1H, J=1.2 Hz), 7.49 (d, 2H, J=8.4Hz), 7.27 (d, 2H, J=8.4 Hz), 7.19 (d, 1H, J=1.2 Hz), 3.66 (m, 3H), 3.62(s, 2H), 2.72 (t, 2H, J=6.9 Hz), 1.99 (t, 2H, J=6.9 Hz), 1.38 (s, 6H).

[4-(8,8-Dimethyl-5-oxo-4-vinyl-5,6,7,8-tetrahydro-naphthalen-2-ylethynyl)-phenyl]-aceticacid methyl ester Intermediate 70

A solution of{4-[8,8-dimethyl-5-oxo-4-trifluoromethanesulfonyloxy-5,6,7,8-tetrahydro-naphthalen-2-ylethynyl]-phenyl}-aceticacid methyl ester (Intermediate 69, 0.233 g, 0.47 mmol) in anhydrous1-methyl 2-pyrrolidinone (3 mL) was sparged with argon, and treated withlithium chloride (0.061 g, 1.45 mmol), tri-2-furylphosphine (0.0071 g,0.031 mmol) and tris(dibenzylideneacetone)dipalladium(0) (0.007 g, 0.015mmol). After 5 minutes, tributyl(vinyl)tin (0.175 g, 0.55 mmol) wasadded and the resulting reaction mixture was stirred at ambienttemperature for 2.5 h. The reaction mixture was diluted with water andextracted with ethyl acetate. The organic phase was washed with brineand water, dried over anhydrous sodium sulfate, filtered and evaporatedin vacuo to a residue that was subjected to flash column chromatographyover silica gel (230-400 mesh) using 10-15% ethyl acetate in hexane asthe eluent to afford the title compound (0.15 g, 86%) as a white solid.

¹H NMR (300 MHz, CDCl₃): δ 7.53 (d, 2H, J=7.8 Hz), 7.51 (d, 1H, J=1.8Hz), 7.50 (d, 1H, J=1.8 Hz), 7.43 (dd, 1H, J=10.5, 17.1 Hz), 7.29 (d,2H, J=7.8 Hz), 5.57 (dd, 1H, J=1.5, 17.1 Hz), 5.33 (dd, 1H, J=1.5, 10.5Hz), 3.71 (s, 3H), 3.66 (s, 2H), 2.74 (t, 2H, J=6.9H-z), 2.00 (t, 2H,J=6.9 Hz), 1.40 (s, 6H).

[4-(8,8-Dimethyl-5-oxo-4-vinyl-5,6,7,8-tetrahydro-naphthalen-2-ylethynyl)-phenyl]-aceticacid Compound 22

A solution of[4-(8,8-dimethyl-5-oxo-4-vinyl-5,6,7,8-tetrahydro-naphthalen-2-ylethynyl)-phenyl]-aceticacid methyl ester (Intermediate 70, 0.082 g, 0.22 mmol) in methanol (3mL) and tetrahydrofuran (3 mL) was treated with a 2M solution of lithiumhydroxide (1.5 mL, 3 mmol) and the resulting reaction mixture wasstirred at ambient temperature for 1.5 h. The volatiles were evaporatedin vacuo, the residue was neutralized with saturated aqueous ammoniumchloride solution and extracted with diethyl ether and ethyl acetate.The organic phase was dried over anhydrous magnesium sulfate, filteredand evaporated in vacuo to afford the title product as a yellow solid(0.065 g, 82%).

¹H NMR (300 MHz, CDCl₃): δ 7.53 (d, 2H, J=8.1 Hz), 7.50 (s, 2H), 7.43(dd, 1H, J=10.8, 17.4 Hz), 7.31 (d, 2H, J=8.1 Hz), 5.57 (dd, 1H, J=1.5,17.4 Hz), 5.33 (dd, 1H, J=1.5, 10.8 Hz), 3.68 (s, 2H), 2.74 (t, 2H,J=6.3 Hz), 1.99 (t, 2H, J=6.3 Hz), 1.39 (s, 6H).

{4-[5-(Cyclopropyl-methyl-amino)-8,8-dimethyl-4-vinyl-5,6,7,8-tetrahydro-naphthalen-2-ylethynyl]-phenyl}-aceticacid methyl ester Intermediate 71

A solution of[4-(8,8-dimethyl-5-oxo-4-vinyl-5,6,7,8-tetrahydro-naphthalen-2-ylethynyl)-phenyl]-aceticacid methyl ester (Intermediate 70, 0.205 g, 0.55 mmol) indichloromethane (4 mL) and acetonitrile (2 mL) was treated withcyclopropyl amine (1 mL, 14.45 mmol). After 5 minutes, acetic acid (1mL) was added followed by sodium cyanoborohydride (0.138 g, 2.2 mmol).The reaction mixture was stirred overnight at ambient temperature. Itwas then diluted with water and saturated aqueous sodium bicarbonatesolution and extracted with ethyl acetate. The combined organic extractwas dried over anhydrous sodium sulfate, filtered and evaporated invacuo to an oil. The oil was dissolved in acetone (10 mL) and treatedwith potassium carbonate (0.227 g, 1.65 mmol) followed by methyl iodide(0.54 mL, 8.7 mmol) and the resulting reaction mixture was stirredovernight at ambient temperature. Diethyl ether was added to thereaction mixture and the precipitated solids were filtered off, thefiltrate was evaporated in vacuo to a residue. Flash columnchromatography over silica gel (230-400 mesh) using 4-5% ethyl acetatein hexane as the eluent afforded the title compound (0.14 g, 60%).

¹H NMR (300 MHz, CDCl₃): δ 7.50 (d, 2H, J=8.4 Hz), 7.47 (s, 1H), 7.45(s, 1H), 7.26 (d, 2H, J=8.4H-z), 7.13 (dd, 1H, J=10.8, 17.7 Hz), 5.47(dd, 1H, J=1.5, 17.7 Hz), 5.11 (dd, 1H, J=1.5, 10.8 Hz), 4.04 (t, 1H,J=5.4 Hz), 3.69 (s, 3H), 3.63 (s, 2H), 2.18 (s, 3H), 2.18-2.14 (m, 1H),2.02 (m, 1H), 1.90-1.75 (m, 2H), 1.58-1.51 (m, 1H), 1.35 (s, 3H), 1.24(s, 3H), 0.39-0.31 (m, 3H), 0.21-0.17 (m, 1H).

{4-[5-(Cyclopropyl-methyl-amino)-8,8-dimethyl-4-vinyl-5,6,7,8-tetrahydro-naphthalen-2-ylethynyl]-phenyl}-aceticacid Compound 23

A solution of{4-[5-(cyclopropyl-methyl-amino)-8,8-dimethyl-4-vinyl-5,6,7,8-tetrahydro-naphthalen-2-ylethynyl]-phenyl}-aceticacid methyl ester (Intermediate 71, 0.14 g, 0.327 mmol) in methanol (3mL) and tetrahydrofuran (3 mL) was treated with a 2M solution of lithiumhydroxide (1.5 mL, 3 mmol) and the resulting reaction mixture wasstirred at ambient temperature for 2 h. The volatiles were evaporated invacuo, the residue was neutralized with saturated aqueous ammoniumchloride solution and extracted with diethyl ether and ethyl acetate.The organic phase was dried over anhydrous magnesium sulfate, filteredand evaporated in vacuo to afford the title product as a white solid(0.135 g, 96%).

¹H NMR (300 MHz, CDCl₃): δ 9.99 (br s, 1H), 7.47 (d, 2H, J=8.1 Hz), 7.44(s, 1H), 7.43 (s, 1H), 7.22 (d, 2H, J=8.1 Hz), 7.11 (dd, 1H, J=10.8,17.1 Hz), 5.47 (dd, 1H, J=0.9, 17.1 Hz), 5.11 (dd, 1H, J=0.9, 10.8 Hz),4.06 (t, 1H, J=6.0 Hz), 3.55 (s, 2H), 2.18 (s, 3H), 2.18-2.15 (m, 1H),2.04 (m, 1H), 1.91-1.77 (m, 2H), 1.56-1.50 (m, 1H), 1.34 (s, 3H), 1.22(s, 3H), 0.42-0.29 (m, 3H), 0.28-0.21 (m, 1H).

4,4-Dimethyl-8-(2-trimethylsilanyl-ethoxymethoxy)-6-trimethylsilanylethynyl-3,4-dihydro-2H-naphthalen-1-oneIntermediate 72

A solution of8-hydroxy-4,4-dimethyl-6-trimethylsilanylethynyl-3,4-dihydro-2H-naphthalen-1-one(Intermediate 66, 1.67 g, 5.8 mmol) in anhydrous benzene was treatedwith triethyl amine (1.41 g, 11.6 mmol) and catalytic amount of4-(dimethylamino)pyridine followed by 2-(trimethylsilyl)ethoxymethylchloride (1.93 g, 11.6 mmol) and the resulting reaction mixture wasrefluxed for 3 days. It was cooled to ambient temperature, diluted withwater and extracted with ethyl acetate. The organic phase was washedwith water and brine, dried over anhydrous magnesium sulfate, filteredand evaporated in vacuo to an oil that was subjected to flash columnchromatography over silica gel (230-400 mesh) using 2-6% ethyl acetatein hexane as the eluent to afford the title product as a yellow oil(1.58 g, 66%).

¹H NMR (300 MHz, CDCl₃): δ 7.16 (d, 1H, J=1.2 Hz), 7.12 (d, 1H, J=1.2Hz), 5.28 (s, 2H), 3.81 (m, 2H), 2.68 (t, 2H, J=6.9 Hz), 1.94 (t, 2H,J=6.9 Hz), 1.34 (s, 6H), 0.96 (m, 2H), 0.27 (s, 9H), 0.00 (s, 9H).

6-Ethynyl-4,4-dimethyl-8-(2-trimethylsilanyl-ethoxymethoxy)-3,4-dihydro-2H-naphthalen-1-oneIntermediate 73

A solution4,4-dimethyl-8-(2-trimethylsilanyl-ethoxymethoxy)-6-trimethylsilanylethynyl-3,4-dihydro-2H-naphthalen-1-one(Intermediate 72, 1.58 g, 3.79 mmol) in methanol (20 mL) was treatedwith potassium carbonate (0.43 g, 3.11 mmol) and the resulting reactionmixture was stirred at ambient temperature overnight. The solvent wasevaporated in vacuo, the residue was diluted with water and extractedwith ethyl acetate. The organic phase was washed with brine, dried overanhydrous magnesium sulfate, filtered and evaporated in vacuo to affordthe title compound (1.28 g, 98%). ¹H NMR (300 MHz, CDCl₃): δ 7.19 (d,1H, J=1.2 Hz), 7.15 (d, 1H, J=1.2 Hz), 5.26 (s, 2H), 3.79 (m, 2H), 3.19(s, 1H), 2.67 (t, 2H, J=6.6 Hz), 1.94 (t, 2H, J=6.6 Hz), 1.33 (s, 6H),0.95 (m, 2H), −0.016 (s, 9H).

{4-[8,8-Dimethyl-5-oxo-4-(2-trimethylsilanyl-ethoxymethoxy)-5,6,7,8-tetrahydro-naphthalen-2-ylethynyl]-phenyl}-aceticacid methyl ester Intermediate 74

Following General Procedure B and using6-ethynyl-4,4-dimethyl-8-(2-trimethylsilanyl-ethoxymethoxy)-3,4-dihydro-2H-naphthalen-1-one(Intermediate 73, 1.28 g, 3.7 mmol), 4-iodo phenyl acetic acid methylester (1.02 g, 3.7 mmol), triethyl amine (30 mL), copper(I)iodide (0.095g, 0.5 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.35 g,0.5 mmol) followed by flash column chromatography over silica gel(230-400 mesh) using 5-15% ethyl acetate in hexane as the eluent, thetitle compound was obtained as a yellow oil (1.61 g, 88%).

¹H NMR (300 MHz, CDCl₃): δ 7.51 (d, 2H, J=8.1 Hz), 7.28 (d, 2H, J=8.1Hz), 7.24 (d, 1H, J=1.5 Hz), 7.19 (d, 1H, J=1.5 Hz), 5.31 (s, 2H), 3.82(m, 2H), 3.70 (s, 3H), 3.65 (s, 2H), 2.69 (t, 21-1, J=6.6 Hz), 1.96 (t,2H, J=6.6 Hz), 1.37 (s, 6H), 0.97 (m, 2H), 0.00 (s, 9H).

{4-[5-(Cyclopropyl-methyl-amino)-8,8-dimethyl-4-(2-trimethylsilanyl-ethoxymethoxy)-5,6,7,8-tetrahydro-naphthalen-2-ylethynyl]-phenyl}-aceticacid methyl ester Intermediate 75

A solution of{4-[8,8-dimethyl-5-oxo-4-(2-trimethylsilanyl-ethoxymethoxy)-5,6,7,8-tetrahydro-naphthalen-2-ylethynyl]-phenyl}-aceticacid methyl ester (Intermediate 74, 0.905 g, 1.84 mmol) indichloromethane (8 mL) and acetonitrile (4 mL) was treated withcyclopropyl amine (4 mL, 57.8 mmol). After 5 minutes, acetic acid (4 mL)was added followed by sodium cyanoborohydride (0.46 g, 7.32 mmol). Thereaction mixture was stirred overnight at ambient temperature. It wasthen diluted with water and saturated aqueous sodium carbonate solutionand extracted with dichloromethane (×2). The combined organic extractwas dried over anhydrous sodium sulfate, filtered and evaporated invacuo to an oil. The oil was dissolved in acetone (15 mL) and treatedwith potassium carbonate (0.745 g, 5.4 mmol) followed by methyl iodide(1.2 mL, 19 mmol) and the resulting reaction mixture was stirredovernight at ambient temperature. The precipitated solids were filteredoff, the filtrate was evaporated in vacuo to a residue. Flash columnchromatography over silica gel (230-400 mesh) using 2-20% ethyl acetatein hexane as the eluent afforded the title compound (0.6 g, 63%).

¹H NMR (300 MHz, CDCl₃): δ 7.49 (d, 2H, J=8.4 Hz), 7.23 (d, 2H, J=8.4Hz), 7.18 (d, 1H, J=1.5 Hz), 7.06 (d, 1H, J=1.5 Hz), 5.21 (s, 2H), 4.03(m, 1H), 3.76 (m, 2H), 3.68 (s, 3H), 3.62 (s, 2H), 2.30 (s, 3H),2.04-1.40 (m, 5H), 1.33 (s, 3H), 1.18 (s, 3H), 0.97 (m, 2H), 0.26-0.01(m, 4H), 0.00 (s, 9H).

4-[5-(Cyclopropyl-methyl-amino)-4-hydroxy-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-ylethynyl]-phenyl}-aceticacid methyl ester Intermediate 76

A solution of{4-[5-(cyclopropyl-methyl-amino)-8,8-dimethyl-4-(2-trimethylsilanyl-ethoxymethoxy)-5,6,7,8-tetrahydro-naphthalen-2-ylethynyl]-phenyl}-aceticacid methyl ester (Intermediate 75, 0.37 g, 0.73 mmol) intetrahydrofuran (12 mL) was treated with 2% sulfuric acid in methanol(14 mL) and the resulting reaction mixture was stirred at ambienttemperature overnight. It was neutralized with saturated sodiumbicarbonate solution and extracted with ethyl acetate. The organic phasewas dried over anhydrous magnesium sulfate, filtered and evaporated invacuo to a residue that after flash column chromatography over silicagel (230-400 mesh) using 5-20% ethyl acetate in hexane as the eluentafford the title product as a white solid (0.295 g, 87%).

¹H NMR (300 MHz, CDCl₃): δ 12.26 (s, 1H), 7.45 (d, 2H, J=8.4 Hz), 7.22(d, 2H, J=8.4 Hz), 6.96 (d, 1H, J=1.5 Hz), 6.69 (d, 1H, J=1.5 Hz), 4.31(m, 1H), 3.67 (s, 3H), 3.61 (s, 2H), 2.23 (s, 3H), 2.23-2.17 (m, 1H),2.05-1.97 (m, 2H), 1.71-1.65 (m, 2H), 1.28 (s, 3H), 1.24 (s, 3H),0.80-0.45 (m, 4H).

4-[5-(Cyclopropyl-methyl-amino)-8,8-dimethyl-4-trifluoromethanesulfonyloxy-5,6,7,8-tetrahydro-naphthalen-2-ylethynyl]-phenyl}-aceticacid methyl ester Intermediate 77

A stirred, cooled (0° C.) solution of4-[5-(cyclopropyl-methyl-amino)-4-hydroxy-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-ylethynyl]-phenyl}-aceticacid methyl ester (Intermediate 76, 0.15 g, 0.275 mmol) in anhydrousdichloromethane was treated with 4-(dimethylamino)pyridine (0.067 g,0.55 mmol) followed by N-phenyltrifluoromethanesulfonimide (0.147 g,0.413 mmol). After stirring at ambient temperature overnight, thereaction mixture was subjected to flash column chromatography oversilica gel (230-400 mesh) using 5-10% ethyl acetate in hexane as theeluent to afford the title compound (0.14 g, 93%).

¹H NMR (300 MHz, CDCl₃): δ 7.51 (d, 2H, J=8.4 Hz), 7.30-7.26 (m, 3H),7.17 (d, 1H, J=1.5 Hz), 4.04 (m, 1H), 3.72 (s, 3H), 3.66 (s, 2H), 2.37(s, 3H), 2.25-2.17 (m, 1H), 2.09-1.74 (m, 3H), 1.59-1.52 (m, 1H), 1.40(s, 3H), 1.23 (s, 3H), 0.28-0.10 (m, 3H), 0.09-0.005 (m, 1H).

8-(Cyclopropyl-methyl-amino)-3-(4-methoxycarbonylmethyl-phenylethynyl)-5,5-dimethyl-5,6,7,8-tetrahydro-naphthalene-1-carboxylicacid ethyl ester Intermediate 78

Following General Procedure E and using4-[5-(cyclopropyl-methyl-amino)-8,8-dimethyl-4-trifluoromethanesulfonyloxy-5,6,7,8-tetrahydro-naphthalen-2-ylethynyl]-phenyl}-aceticacid methyl ester (Intermediate 77, 0.14 g, 0.26 mmol), palladiumacetate (0.013 g, 0.06 mmol), 1,3-bis(diphenylphosphino)propane (0.025g, 0.061 mmol), N,N-dimethylformamide (4 mL), ethanol (1.5 mL) andtriethyl amine (1.5 mL) followed by flash column chromatography oversilica gel (230-400 mesh) using 7-10% ethyl acetate in hexane as theeluent, the title compound was obtained (0.09 g, 75%).

¹H NMR (300 MHz, CDCl₃): δ 7.49 (d, 1H, J=1.8 Hz), 7.47 (d, 2H, J=8.1Hz), 7.30 (d, 1H, J=1.8 Hz), 7.25 (d, 2H, J=8.1 Hz), 4.33 (m, 1H),4.28-4.13 (m, 2H), 3.70 (s, 3H), 3.63 (s, 2H), 2.06-1.93 (2m, 6H),1.72-1.66 (m, 2H), 1.36 (t, 3H, J=7.2 Hz), 1.31 (s, 3H), 1.29 (s, 3H),0.60-0.40 (m, 1H), 0.40-0.25 (m, 2H), 0.15-0.00 (m, 1H).

3-(4-Carboxymethyl-phenylethynyl)-8-(cyclopropyl-methyl-amino)-5,5-dimethyl-5,6,7,8-tetrahydro-naphthalene-1-carboxylicacid ethyl ester Compound 24

A solution of8-(cyclopropyl-methyl-amino)-3-(4-methoxycarbonylmethyl-phenylethynyl)-5,5-dimethyl-5,6,7,8-tetrahydro-naphthalene-1-carboxylicacid ethyl ester (Intermediate 78, 0.09 g, 0.19 mmol) in ethanol (2 mL),tetrahydrofuran (3 mL) and water (1.5 mL) was treated with lithiumhydroxide (0.11 g, 2.62 mmol) and the resulting reaction mixture wasstirred at ambient temperature for 2 h. The volatiles were evaporated invacuo to a residue that was neutralized with saturated aqueous ammoniumchloride solution and extracted with ethyl acetate. The organic phasewas washed with water and brine, and dried over anhydrous magnesiumsulfate, filtered and evaporated in vacuo to afford the title product asa white solid (0.085 g, 94%).

¹H NMR (300 MHz, CDCl₃): δ 7.49 (d, 1H, J=1.8 Hz), 7.46 (d, 2H, J=8.1Hz), 7.30 (d, 1H, J=1.8 Hz), 7.22 (d, 2H, J=8.1 Hz), 4.32 (m, 1H),4.30-4.10 (m, 2H), 3.58 (s, 2H), 2.06-1.93 (2m, 6H), 1.72-1.65 (m, 2H),1.35 (t, 3H, J=7.0 Hz), 1.34 (s, 3H), 1.29 (s, 3H), 0.60-0.40 (m, 1H),0.40-0.25 (m, 2H), 0.15-0.00 (m, 1H).

2-Bromo-5-(cyclopropyl-methyl-amino)-8,8-dimethyl-4-methoxy-5,6,7,8-tetrahydronaphthaleneIntermediate 79

A solution of6-bromo-8-methoxy-4,4-dimethyl-3,4-dihydro-2H-naphthalen-1-one(Intermediate 64, 1.08 g, 3.81 mmol) in dichloromethane (8 mL) andacetonitrile (4 mL) was treated with cyclopropyl amine (5 mL, 72.3mmol). After 5 minutes, acetic acid (5 mL) was added followed by sodiumcyanoborohydride (0.96 g, 15.26 mmol). The reaction mixture was stirredfor 2 days at ambient temperature. It was then diluted with water andsaturated aqueous sodium carbonate solution and extracted with ethylacetate. The combined organic extract was dried over anhydrous sodiumsulfate, filtered and evaporated in vacuo to an oil. The oil wasdissolved in acetone (20 mL) and treated with potassium carbonate (1.58g, 11.43 mmol) followed by methyl iodide (20.1 mL, 33 mmol) and theresulting reaction mixture was stirred overnight at ambient temperature.Diethyl ether was added and the precipitated solids were filtered off,the filtrate was evaporated in vacuo to a residue. Flash columnchromatography over silica gel (230-400 mesh) using 2.5-10% ethylacetate in hexane as the eluent afforded the title compound (1.08 g,84%).

¹H NMR (300 MHz, CDCl₃): δ 7.08 (d, 1H, J=1.8 Hz), 6.78 (d, 1H, J=1.8Hz), 3.97 (m, 1H), 3.79 (s, 3H), 2.30 (s, 3H), 2.04-1.82 (m, 3H),1.65-1.27 (m, 2H), 1.30 (s, 3H), 1.16 (s, 3H), 0.30-0.22 (m, 2H),0.07-0.00 (m, 2H).

5-(Cyclopropyl-methyl-amino)-8,8-dimethyl-4-methoxy-2-trimethylsilanylethynyl-5,6,7,8-tetrahydro-naphthaleneIntermediate 80

Following General Procedure D and using2-bromo-5-(cyclopropyl-methylamino)-8,8-dimethyl-4-methoxy-5,6,7,8-tetrahydro-naphthalene(Intermediate 79, 1.08 g, 3.2 mmol), triethyl amine (5 mL),copper(I)iodide (0.061 g, 0.32 mmol), trimethylsilyl acetylene (3 mL,21.1 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.225 g,0.32 mmol) followed by flash column chromatography over silica gel(230-400 mesh) using hexane-10% ethyl acetate in hexane as the eluent,the title compound (0.87 g, 80%) was obtained.

¹H NMR (300 MHz, CDCl₃): δ 7.09 (d, 1H, J=1.5 Hz), 6.73 (d, 1H, J=1.5Hz), 3.99 (m, 1H), 3.79 (s, 3H), 2.28 (s, 3H), 2.02-1.80 (m, 3H),1.65-1.26 (2m, 2H), 1.31 (s, 3H), 1.16 (s, 3H), 0.26 (s, 9H), 0.26-0.00(m, 2H), 0.00-−0.01 (m, 2H).

5-(Cyclopropyl-methyl-amino)-2-ethynyl-8,8-dimethyl-4-methoxy-5,6,7,8-tetrahydronaphthaleneIntermediate 81

A solution of5-(cyclopropyl-methyl-amino)-8,8-dimethyl-4-methoxy-2-trimethylsilanylethynyl-5,6,7,8-tetrahydro-naphthalene(Intermediate 80, 0.87 g, 2.45 mmol) in methanol (20 mL) was treatedwith potassium carbonate (0.4 g, 2.89 mmol) and the resulting reactionmixture was stirred at ambient temperature overnight. The solvent wasevaporated in vacuo, the residue was diluted with water and extractedwith diethyl ether. The organic phase was washed with brine, dried overanhydrous magnesium sulfate, filtered and evaporated in vacuo to affordthe title compound (0.635 g, 92%).

¹H NMR (300 MHz, CDCl₃): δ 7.16 (d, 1H, J=1.4 Hz), 6.79 (d, 1H, J=1.4Hz), 4.04 (m, 1H), 3.82 (s, 3H), 2.32 (s, 3H), 2.03-1.95 (m, 2H),1.90-1.80 (m, 1H), 1.70-1.55 (m, 1H), 1.45-1.35 (m, 1H), 1.34 (s, 3H),1.19 (s, 3H), 0.40-0.20 (m, 2H), 0.07-0.00 (m, 21-1).

{4-[5-(Cyclopropyl-methyl-amino)-4-methoxy-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-ylethynyl]-phenyl}-aceticacid methyl ester Intermediate 82

Following General Procedure B and using5-(cyclopropyl-methyl-amino)-2-ethynyl-8,8-dimethyl-4-methoxy-5,6,7,8-tetrahydro-naphthalene(Intermediate 81, 0.065 g, 0.23 mmol), methyl-4-iodophenylacetate (0.063g, 0.23 mmol), triethyl amine (8 mL), copper(I)iodide (0.018 g, 0.093mmol) and dichlorobis(triphenylphosphine)palladium(I) (0.065 g, 0.093mmol) followed by flash column chromatography over silica gel (230-400mesh) using 5-20% ethyl acetate in hexane as the eluent, the titlecompound was obtained as a yellow solid (0.09 g, 90%).

¹H NMR (300 MHz, CDCl₃): δ 7.50 (d, J=8.2 Hz, 2H), 7.26 (d, J=8.2 Hz,2H), 7.17 (d, J=1.2 Hz, 1H), 6.81 (d, J=1.2 Hz, 1H), 4.04 (bs, 1H), 3.82(s, 3H), 3.70 (s, 3H), 3.64 (s, 2H), 2.32 (s, 3H), 2.05-1.94 (m, 2H),1.90-1.80 (m, 1H), 1.70-1.58 (m, 1H), 1.45-1.35 (m, 1H), 1.38 (s, 3H),1.20 (s, 3H), 0.38-0.20 (m, 2H), 0.18-0.02 (m, 2H).

{4-[5-(Cyclopropyl-methyl-amino)-4-methoxy-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-ylethynyl]-phenyl}-aceticacid Compound 25

A solution of{4-[5-(cyclopropyl-methyl-amino)-4-methoxy-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-ylethynyl]-phenyl}-aceticacid methyl ester (Intermediate 82, 0.090 g, 0.208 mmol) in methanol (3mL) and tetrahydrofuran (2 mL) was treated with a 1.9 M solution oflithium hydroxide (1.5 mL, 2.8 mmol) and the resulting reaction mixturewas stirred at ambient temperature for 2 h. The reaction mixture wasconcentrated, neutralized with ammonium chloride and extracted withethyl acetate. The organic phase was washed with water and brine, anddried over anhydrous magnesium sulfate, filtered and evaporated in vacuoto a residue that was subjected to flash column chromatography oversilica gel (230-400 mesh) using 5-10% methanol in ethyl acetate as theeluent to afford the title product as a white amorphous solid (0.062 g,60%).

¹H NMR (300 MHz, CDCl₃): 7.46 (d, J=8.2 Hz, 2H), 7.28 (d, J=8.2 Hz, 2H),7.18 (d, J=1.2 Hz, 1H), 6.81 (d, J=1.2 Hz, 1H), 4.27 (bs, 1H), 3.81 (s,3H), 3.58 (s, 2H), 2.42 (s, 3H), 2.28-2.18 (m, 1H), 2.15-1.88 (m, 2H),1.75-1.65 (m, 1H), 1.45-1.38 (m, 1H), 1.32 (s, 3H), 1.17 (s, 3H),0.75-0.65 (m, 1H), 0.55-0.42 (m, 2H), 0.25-0.15 (m, 1H).

{4-[5-(Cyclopropyl-methyl-amino)-4-methoxy-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-ylethynyl]-2-fluoro-phenyl}-aceticacid methyl ester Intermediate 83

Following General Procedure B and using5-(cyclopropyl-methyl-amino)-2-ethynyl-8,8-dimethyl-4-methoxy-5,6,7,8-tetrahydro-naphthalene(Intermediate 81, 0.085 g, 0.3 mmol),methyl-2-fluoro-4-iodophenylacetate (0.088 g, 0.3 mmol), triethyl amine(8 mL), copper(I)iodide (0.019 g, 0.1 mmol) anddichlorobis(triphenylphosphine)palladium(II) (0.07 g, 0.1 mmol) followedby flash column chromatography over silica gel (230-400 mesh) using5-20% ethyl acetate in hexane as the eluent, the title compound wasobtained as a yellow solid (0.12 g, 89%).

¹H NMR (300 MHz, CDCl₃): δ 7.36-7.17 (m, 4H), 6.81 (d, J=1.2 Hz, 1H),4.12 (bs, 1H), 3.83 (s, 3H), 3.72 (s, 3H), 3.69 (s, 2H), 2.33 (s, 3H),2.08-1.98 (m, 2H), 1.98-1.88 (m, 1H), 1.75-1.60 (m, 1H), 1.45-1.35 (m,1H), 1.35 (s, 3H), 1.19 (s, 3H), 0.35-0.25 (m, 2H), 0.15-0.05 (m, 1H).

{4-[5-(Cyclopropyl-methyl-amino)-4-methoxy-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-ylethynyl]-2-fluoro-phenyl}-aceticacid Compound 26

A solution of{4-[5-(cyclopropyl-methyl-amino)-4-methoxy-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-ylethynyl]-2-fluoro-phenyl}-aceticacid methyl ester (Intermediate 83, 0.12 g, 0.27 mmol) in methanol (4mL) and tetrahydrofuran (4 mL) was treated with a 2 M solution oflithium hydroxide (2 mL, 4 mmol) and the resulting reaction mixture wasstirred at ambient temperature for 2 h. The reaction mixture wasconcentrated, neutralized with ammonium chloride and extracted withethyl acetate. The organic phase was washed with water and brine, anddried over anhydrous magnesium sulfate, filtered and evaporated in vacuoto a residue that was subjected to flash column chromatography oversilica gel (230-400 mesh) using 5-8% methanol in ethyl acetate as theeluent to afford the title product as a white amorphous solid (0.041 g,35%).

¹H NMR (300 MHz, CDCl₃): δ 7.35-7.15 (m, 4H), 6.81 (d, J=1.2 Hz, 1H),4.31 (bs, 1H), 3.82 (s, 3H), 3.64 (s, 2H), 2.46 (s, 3H), 2.32-2.22 (m,1H), 2.18-1.88 (m, 2H), 1.78-1.65 (m, 1H), 1.50-1.40 (m, 1H), 1.32 (s,3H), 1.17 (s, 3H), 0.80-0.70 (m, 1H), 0.58-0.40 (m, 2H), 0.28-0.18 (m,1H).

2-{4-[5-(Cyclopropyl-methyl-amino)-4-methoxy-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-ylethynyl]-phenyl}-propionicacid methyl ester Intermediate 84

Following General Procedure B and using5-(cyclopropyl-methyl-amino)-2-ethynyl-8,8-dimethyl-4-methoxy-5,6,7,8-tetrahydro-naphthalene(Intermediate 81, 0.085 g, 0.30 mmol), methyl-2-(4-iodophenyl)propionate(Reagent 1, 0.087 g, 0.3 mmol), triethyl amine (8 mL), copper(I)iodide(0.019 g, 0.1 mmol) and dichlorobis(triphenylphosphine)palladium(II)(0.07 g, 0.1 mmol) followed by flash column chromatography over silicagel (230-400 mesh) using 5-20% ethyl acetate in hexane as the eluent,the title compound was obtained as a yellow solid (0.115 g, 86%).

¹H NMR (300 MHz, CDCl₃): δ 7.50 (d, 2H, J=8.1 Hz), 7.28 (d, 2H, J=8.1Hz), 7.16 (d, 1H, J=1.2 Hz), 6.81 (d, 1H, J=1.2 Hz), 4.04 (m, 1H), 3.83(s, 3H), 3.74 (q, 1H, J=6.9 Hz), 3.67 (s, 3H), 2.31 (s, 3H), 2.03-1.98(m, 2H), 1.89-1.83 (m, 1H), 1.68-1.59 (m, 1H), 1.51 (d, 3H, J=6.9 Hz),1.42-1.27 (m, 1H), 1.35 (s, 3H), 1.20 (s, 3H), 0.31-0.23 (m, 2H),0.07-0.008 (m, 2H).

2-{4-[5-(Cyclopropyl-methyl-amino)-4-methoxy-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-ylethynyl]-phenyl}-propionicacid Compound 27

A solution of2-{4-[5-(cyclopropyl-methyl-amino)-4-methoxy-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-ylethynyl]-phenyl}-propionicacid methyl ester (Intermediate 84, 0.115 g, 0.26 mmol) in methanol (3mL) and tetrahydrofuran (2 mL) was treated with a 3M solution ofpotassium hydroxide (1 mL, 3 mmol) and the resulting reaction mixturewas stirred at ambient temperature overnight. The reaction mixture wasneutralized with 5% aqueous hydrochloric acid and extracted with ethylacetate. The organic phase was washed with water and brine, and driedover anhydrous magnesium sulfate, filtered and evaporated in vacuo to aresidue that was subjected to flash column chromatography over silicagel (230-400 mesh) using 8% methanol in ethyl acetate as the eluent toafford the title product as a yellow solid (0.062 g, 56%).

¹H NMR (300 MHz, CDCl₃): δ 7.50 (d, 2H, J=8.1 Hz), 7.32 (d, 2H, J=8.1Hz), 7.17 (s, 1H), 6.80 (s, 1H), 4.23 (m, 1H), 3.80 (s, 3H), 3.68 (q,1H, J=7.2 Hz), 2.38 (s, 3H), 2.22-2.18 (m, 1H), 2.07-1.87 (m, 2H),1.70-1.57 (m, 1H), 1.47 (d, 3H, J=7.2 Hz), 1.38-1.27 (m, 1H), 1.31 (s,3H), 1.16 (s, 3H), 0.65-0.62 (m, 1H), 0.41-0.35 (m, 2H), 0.17-0.00 (m,1H).

2-{4-[5-(Cyclopropyl-methyl-amino)-4-methoxy-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-ylethynyl]-phenyl}-2-methyl-propionicacid methyl ester Intermediate 85

Following General Procedure B and using5-(cyclopropyl-methyl-amino)-2-ethynyl-8,8-dimethyl-4-methoxy-5,6,7,8-tetrahydro-naphthalene(Intermediate 81, 0.090 g, 0.32 mmol),methyl-2-(4-iodophenyl)-2-methyl-propionate (Reagent 2, 0.097 g, 0.3mmol), triethyl amine (8 mL), copper(I)iodide (0.019 g, 0.1 mmol) anddichlorobis(triphenylphosphine)palladium(II) (0.07 g, 0.1 mmol) followedby flash column chromatography over silica gel (230-400 mesh) using5-20% ethyl acetate in hexane as the eluent, the title compound wasobtained as a solid (0.09 g, 78%).

¹H NMR (300 MHz, CDCl₃): δ 7.50 (d, 2H, J=8.1 Hz), 7.31 (d, 2H, J=8.1Hz), 7.16 (d, 1H, J=1.2 Hz), 6.80 (d, 1H, J=1.2 Hz), 4.03 (m, 1H), 3.83(s, 3H), 3.66 (s, 3H), 2.31 (s, 3H), 2.01-1.97 (m, 2H), 1.89-1.83 (m,1H), 1.68-1.59 (m, 1H), 1.59 (s, 6H), 1.42-1.27 (m, 1H), 1.34 (s, 3H),1.20 (s, 3H), 0.31-0.22 (m, 2H), 0.07-0.00 (m, 2H).

2-{4-[5-(Cyclopropyl-methyl-amino)-4-methoxy-8,8-dimethyl-5,6,7,8-tetrahydronaphthalen-2-ylethynyl]-phenyl}-2-methyl-propionicacid Compound 28

A solution of2-{4-[5-(cyclopropyl-methyl-amino)-4-methoxy-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-ylethynyl]-phenyl}-2-methyl-propionicacid methyl ester (Intermediate 85, 0.09 g, 0.196 mmol) in methanol (3mL) and tetrahydrofuran (2 mL) was treated with a 3M solution ofpotassium hydroxide (1.5 mL, 4.5 mmol) and the resulting reactionmixture was stirred at ambient temperature for 3 days. The reactionmixture was neutralized with 5% aqueous hydrochloric acid and extractedwith ethyl acetate. The organic phase was washed with water and brine,and dried over anhydrous sodium sulfate, filtered and evaporated invacuo to a residue that was subjected to flash column chromatographyover silica gel (230-400 mesh) using 5% methanol in ethyl acetate as theeluent to afford the title product as a yellow solid (0.057 g, 65%).

¹H NMR (300 MHz, CDCl₃): δ 7.46 (d, 2H, J=8.4 Hz), 7.37 (d, 2H, J=8.4Hz), 7.18 (d, 1H, J=1.2 Hz), 6.81 (d, 1H, J=1.2 Hz), 4.22 (m, 1H), 3.83(s, 3H), 2.38 (s, 3H), 2.19-1.90 (m, 3H), 1.71-1.56 (m, 1H), 1.56 (s,6H), 1.45-1.33 (m, 1H), 1.33 (s, 3H), 1.17 (s, 3H), 0.70-0.50 (m, 1H),0.38-0.25 (m, 2H), 0.16-0.00 (m, 1H).

(E)-3-{4-[5-(Cyclopropyl-methyl-amino)-4-methoxy-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-ylethynyl]-phenyl}-acrylicacid methyl ester Intermediate 86

Following General Procedure B and using5-(cyclopropyl-methyl-amino)-2-ethynyl-8,8-dimethyl-4-methoxy-5,6,7,8-tetrahydro-naphthalene(Intermediate 81, 0.095 g, 0.336 mmol), methyl-4-iodocinnamate (Reagent4, 0.097 g, 0.336 mmol), triethyl amine (8 mL), copper(I)iodide (0.019g, 0.1 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.07 g,0.1 mmol) followed by flash column chromatography over silica gel(230-400 mesh) using 5-15% ethyl acetate in hexane as the eluent, thetitle compound was obtained as a white solid (0.12 g, 80%).

¹H NMR (300 MHz, CDCl₃): δ 7.68 (d, 1H, J=15.9 Hz), 7.53 (Abq, 4H, J=8.4Hz), 7.19 (s, 1H), 6.83 (s, 1H), 7.46 (d, 1H, J=15.9 Hz), 4.04 (m, 1H),3.84 (s, 3H), 3.82 (s, 3H), 2.32 (s, 3H), 2.04-1.97 (m, 2H), 1.90-1.83(m, 1H), 1.68-1.60 (m, 1H), 1.43-1.27 (m, 1H), 1.36 (s, 3H), 1.21 (s,3H), 0.32-0.23 (m, 2H), 0.08-0.00 (m, 2H).

(E)-3-{4-[5-(Cyclopropyl-methyl-amino)-4-methoxy-8,8-dimethyl-5,6,78-tetrahydro-naphthalen-2-ylethynyl]-phenyl}-acrylicacid Compound 29

A solution of(E)-3-{4-[5-(cyclopropyl-methyl-amino)-4-methoxy-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-ylethynyl]-phenyl}-acrylicacid methyl ester (Intermediate 86, 0.12 g, 0.27 mmol) in methanol (4mL) and tetrahydrofuran (3 mL) was treated with a 3M solution ofpotassium hydroxide (1 mL, 3 mmol) and the resulting reaction mixturewas stirred at ambient temperature overnight. The reaction mixture wasneutralized with 5% aqueous hydrochloric acid and extracted with ethylacetate. The organic phase was washed with water and brine, and driedover anhydrous magnesium sulfate, filtered and evaporated in vacuo to aresidue that was subjected to flash column chromatography over silicagel (230-400 mesh) using 5% methanol in ethyl acetate as the eluent toafford the title product as a white solid (0.041 g, 35%).

¹H NMR (300 MHz, CDCl₃): δ 7.58 (d, 1H, J=16.2 Hz), 7.44 (Abq, 4H), 7.13(s, 1H), 6.77 (s, 1H), 7.45 (d, 1H, J=16.2 Hz), 4.05 (m, 1H), 3.79 (s,3H), 2.42 (s, 3H), 2.19-1.97 (m, 2H), 1.67-1.45 (m, 1H), 1.45-1.37 (m,1H), 1.37-1.20 (m, 1H), 1.30 (s, 3H), 1.12 (s, 3H), 0.80-0.60 (m, 1H),0.50-0.30 (m, 2H), 0.20-0.00 (m, 1H).

(E)-3-{4-[5-(Cyclopropyl-methyl-amino)-4-methoxy-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-ylethynyl]-cyclohexa-2,4-dienyl}-2-methyl-acrylicacid ethyl ester Intermediate 87

Following General Procedure B and using5-(cyclopropyl-methyl-amino)-2-ethynyl-8,8-dimethyl-4-methoxy-5,6,7,8-tetrahydro-naphthalene(Intermediate 81 0.08 g, 0.28 mmol),(E)-3-(4-iodo-phenyl)-2-methyl-acrylic acid ethyl ester (Reagent 7, 0.09g, 0.28 mmol), triethyl amine (8 mL), copper(I)iodide (0.019 g, 0.1mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.07 g, 0.1mmol) followed by flash column chromatography over silica gel (230-400mesh) using 5-10% ethyl acetate in hexane as the eluent, the titlecompound was obtained as a white solid (0.12 g, 90%).

¹H NMR (300 MHz, CDCl₃): δ 7.67 (d, 1H, J=1.2 Hz), 7.57 (d, 2H, J=8.4Hz), 7.40 (d, 2H, J=8.4 Hz), 7.19 (d, 1H, J=1.5 Hz), 6.83 (d, 1H, J=1.5Hz), 4.28 (q, 2H, J=7.2 Hz), 4.04 (m, 1H), 3.84 (s, 3H), 2.32 (s, 3H),2.15 (d, 3H, J=1.2 Hz), 2.03-1.83 (m, 3H), 1.68-1.50 (m, 1H), 1.45-1.20(m, 1H), 1.36 (s, 3H), 1.35 (t, 3H, J=7.2 Hz), 1.20 (s, 3H), 0.32-0.23(m, 2H), 0.08-0.00 (m, 21-1).

(E)-3-{4-[5-(Cyclopropyl-methyl-amino)-4-methoxy-8,8-dimethyl-5,6,7,8-tetrahydronaphthalen-2-ylethynyl]-cyclohexa-2,4-dienyl}-2-methyl-acrylicacid Compound 30

A solution of(E)-3-{4-[5-(cyclopropyl-methyl-amino)-4-methoxy-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-ylethynyl]-cyclohexa-2,4-dienyl}-2-methyl-acrylicacid methyl ester (Intermediate 87, 0.12 g, 0.25 mmol) in methanol (3mL) and tetrahydrofuran (2 mL) was treated with a 3M solution ofpotassium hydroxide (1 mL, 3 mmol) and the resulting reaction mixturewas stirred at ambient temperature overnight. The reaction mixture wasneutralized with 5% aqueous hydrochloric acid and extracted with ethylacetate. The organic phase was washed with water and brine, and driedover anhydrous magnesium sulfate, filtered and evaporated in vacuo to aresidue that was recrystallized from hot acetonitrile to afford thetitle product as a white solid (0.055 g, 49%).

¹H NMR (300 MHz, CDCl₃): δ 7.78 (d, 1H, J=1.2 Hz), 7.57 (d, 2H, J=8.1Hz), 7.43 (d, 2H, J=8.1 Hz), 7.29 (d, 1H, J=1.5 Hz), 6.93 (d, 1H, J=1.5Hz), 4.93 and 4.70 (2m, 1H), 3.97 (s, 3H), 2.54 (s, 3H), 2.40-1.60 (m,4H), 2.16 (d, 3H, J=1.2 Hz), 1.46-1.23 (m, 1H), 1.46 (s, 3H), 1.23 (s,3H), 0.90-0.20 (m, 4H).

Cyclopropyl-(3-iodo-benzyl)-amine Intermediate 88

A solution of 3-iodobenzyl bromide (Aldrich, 3.2 g, 10.77 mmol) inethanol (20 mL) was treated with cyclopropyl amine (7 mL, 101.5 mmol)and the resulting reaction mixture was stirred over 3 days at ambienttemperature. The volatiles were evaporated in vacuo, the residue wasdiluted with ethyl acetate and washed with saturated, aqueous sodiumbicarbonate solution, water and brine, dried over anhydrous sodiumsulfate, filtered and evaporated in vacuo to an oil that was subjectedto flash column chromatography over silica gel (230-400 mesh) using10-20% ethyl acetate in hexane as the eluent afford the title product(2.4 g, 81%).

¹H NMR (300 MHz, CDCl₃): δ 7.67 (s, 1H), 7.58 (d, 1H, J=9.0 Hz), 7.27(d, 1H, J=6.0 Hz), 7.05 (dd, 1H, J=6.0, 9.0 Hz), 3.78 (s, 2H), 2.13 (m,1H), 1.76 (br s, 1H), 0.50-0.35 (m, 4H).

Cyclopropyl-(3-iodo-benzyl)-methyl-amine Intermediate 89

A solution of cyclopropyl-(3-iodo-benzyl)-amine (Intermediate 88, 4.1 g,151 mmol) in acetone (20 mL) was treated with potassium carbonate (2.07g, 15 mmol) and methyl iodide (1.4 mL, 22.5 mmol) and the resultingreaction mixture was stirred at ambient temperature for 1 h. Diethylether was added, the solids were filtered off and filtrate wasevaporated to a residue that was subjected to flash columnchromatography over silica gel (230-400 mesh) using 10% ethyl acetate inhexane as the eluent to afford the title compound (3.3 g, 77%).

¹H NMR (300 MHz, CDCl₃): δ 7.62 (d, 1H, J=1.5 Hz), 7.55 (dd, 1H, J=1.5,7.8 Hz), 7.21 (dd, 1H, J=1.5, 7.8 Hz), 7.01 (t, 1H, J=7.8 Hz), 3.61 (s,2H), 2.22 (s, 3H), 1.69 (m, 1H), 0.50-0.38 (m, 4H).

Cyclopropyl-methyl-(3-trimethylsilanylethynyl-benzyl)-amine Intermediate90

Following General Procedure D and usingcyclopropyl-(3-iodo-benzyl)-methyl-amine (Intermediate 89, 0.97 g, 3.4mmol), triethyl amine (10 mL), copper(I)iodide (0.051 g, 0.27 mmol),trimethylsilyl acetylene (2 mL, 14 mmol) anddichlorobis(triphenylphosphine)palladium(II) (0.19 g, 0.27 mmol)followed by flash column chromatography over silica gel (230-400 mesh)using hexane-5% ethyl acetate in hexane as the eluent, the titlecompound (0.695 g, 80%) was obtained.

¹H NMR (300 MHz, CDCl₃): δ 7.37-7.31 (m, 2H), 7.25-7.20 (m, 2H), 3.61(s, 2H), 2.22 (s, 3H), 1.69 (m, 1H), 0.50-0.32 (m, 4H), 0.25 (s, 9H).

Cyclopropyl-(3-ethynyl-benzyl)-methyl-amine Intermediate 91

A solution cyclopropyl-methyl-(3-trimethylsilanylethynyl-benzyl)-amine(Intermediate 90, 0.355 g, 1.38 mmol) in methanol (10 mL) was treatedwith potassium carbonate (0.13 g, 0.95 mmol) and the resulting reactionmixture was stirred at ambient temperature overnight. The solvent wasevaporated in vacuo, the residue was diluted with water and extractedwith diethyl ether. The organic phase was washed with brine, dried overanhydrous magnesium sulfate, filtered and evaporated in vacuo to affordthe title compound (0.22 g, 86%).

¹H NMR (300 MHz, CDCl₃): δ 7.41-7.35 (m, 2H), 7.26-7.23 (m, 2H), 3.63(s, 2H), 3.05 (s, 1H), 2.23 (s, 3H), 1.70 (m, 1H), 0.48-0.40 (m, 4H).

(E)-3-(4-{3-[(Cyclopropyl-methyl-amino)-methyl]-phenylethynyl}-phenyl)-acrylicacid methyl ester Intermediate 92

Following General Procedure B and usingcyclopropyl-(3-ethynyl-benzyl)-methyl-amine (Intermediate 91, 0.060 g,0.32 mmol), methyl-4-iodo-cinnamate (Reagent 4, 0.093 g, 0.32 mmol),triethyl amine (8 mL), copper(I)iodide (0.015 g, 0.08 mmol) anddichlorobis(triphenylphosphine)palladium(II) (0.056 g, 0.08 mmol)followed by flash column chromatography over silica gel (230-400 mesh)using 5-15% ethyl acetate in hexane as the eluent, the title compoundwas obtained (0.11 g, 100%).

¹H NMR (300 MHz, CDCl₃): δ 7.66 (d, 2H, J=16.2 Hz), 7.54-7.39 (m, 2H),7.31-7.25 (m, 2H), 6.43 (d, 2H, J=16.2 Hz), 3.80 (s, 3H), 3.65 (s, 2H),2.25 (s, 3H), 1.72 (m, 1H), 0.49-0.42 (m, 4H).

(E)-3-(4-{3-[(Cyclopropyl-methyl-amino)-methyl]-phenylethynyl}-phenyl)-acrylicacid Compound 31

A solution of(E)-3-(4-{3-[(cyclopropyl-methyl-amino)-methyl]-phenylethynyl}-phenyl)-acrylicacid methyl ester (Intermediate 92, 0.11 g, 0.32 mmol) in methanol (3mL) and tetrahydrofuran (2 mL) was treated with a 3M solution ofpotassium hydroxide (1 mL, 3 mmol) and the resulting reaction mixturewas stirred at ambient temperature for 2 days. The reaction mixture wasneutralized with 5% aqueous hydrochloric acid and extracted with ethylacetate. The organic phase was washed with water and brine, and driedover anhydrous sodium sulfate, filtered and evaporated in vacuo to aresidue that was subjected to flash column chromatography over silicagel (230-400 mesh) using 10% methanol in ethyl acetate as the eluent toafford the title product as a yellow solid (0.038 g, 36%).

¹H NMR (300 MHz, CD₃OD): δ 7.61-7.38 (m, 9H), 6.53 (d, 1H, J=15.9 Hz),3.93 (s, 2H), 2.48 (s, 3H), 2.09 (m, 1H), 0.64-0.61 (m, 4H).

3-(4-{3-[(Cyclopropyl-methyl-amino)-methyl]-phenylethynyl}-phenyl)-but-2-enoicacid ethyl ester Intermediate 93

Following General Procedure B and usingcyclopropyl-(3-ethynyl-benzyl)-methyl-amine (Intermediate 91, 0.12 g,0.64 mmol), 3-(4-iodo-phenyl)-but-2Z-enoic acid ethyl ester (Reagent 5,0.2 g, 0.64 mmol), triethyl amine (8 mL), copper(I)iodide (0.012 g,0.063 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.045 g,0.064 mmol) followed by flash column chromatography over silica gel(230-400 mesh), the title compound was obtained (0.17 g, 70%).

¹H NMR (300 MHz, CDCl₃): δ 7.52-7.40 (m, 4H), 7.31-7.18 (m, 4H), 5.91(s, 1H), 4.01 (q, J=7.1 Hz, 2H), 3.66 (s, 2H), 2.26 (s, 3H), 2.17 (s,3H), 1.74-1.70 (m, 1H), 1.10 (t, J=7.1 Hz, 3H), 0.50-0.43 (m, 4H).

3-(4-{3-[(Cyclopropyl-methyl-amino)-methyl]-phenylethynyl}-phenyl)-but-2-enoicacid Compound 32

A solution of3-(4-{3-[(cyclopropyl-methyl-amino)-methyl]-phenylethynyl}-phenyl)-but-2-enoicacid ethyl ester (Intermediate 93, 0.17 g, 0.46 mmol) in ethanol (3 mL)and tetrahydrofuran (3 mL) was treated with a 3.4M solution of potassiumhydroxide (1 mL, 3.4 mmol) and the resulting reaction mixture wasstirred at ambient temperature for 36 h. The reaction mixture wasextracted with diethyl ether, and the aqueous phase was neutralized with10% aqueous hydrochloric acid and evaporated to a solid. The solid wassubjected to flash column chromatography using ethyl acetate as theeluent to afford the title product as a white solid (0.05 g, 32%). ¹HNMR (300 MHz, CDCl₃): δ 7.49-7.43 (m, 4H), 7.32-7.20 (m, 4H), 5.93 (s,1H), 3.70 (s, 2H), 2.29 (s, 3H), 2.17 (s, 3H), 1.76-1.73 (m, 1H),0.50-0.48 (m, 4H).

3-(4-{3-[(Cyclopropyl-methyl-amino)-methyl]-phenylethynyl}-phenyl)-2-methyl-acrylicacid ethyl ester Intermediate 94

Following General Procedure B and usingcyclopropyl-(3-ethynyl-benzyl)-methyl-amine (Intermediate 91, 0.1 g,0.54 mmol), (E)-3-(4-iodo-phenyl)-2-methyl-acrylic acid ethyl ester(Reagent 7, 0.17 g, 0.54 mmol), triethyl amine (10 mL), copper(I)iodide(0.019 g, 0.1 mmol) and dichlorobis(triphenylphosphine)palladium(II)(0.071 g, 0.1 mmol) followed by flash column chromatography over silicagel (230-400 mesh) using 2-10% ethyl acetate in hexane as the eluent,the title compound was obtained (0.15 g, 75%). ¹H NMR (300 MHz, CDCl₃):δ 7.66-7.25 (m, 9H), 4.27 (q, J=7.3 Hz, 2H), 3.65 (s, 2H), 2.25 (s, 3H),2.13 (d, J=1.2 Hz, 3H), 1.75-1.65 (m, 1H), 1.35 (t, J=7.3 Hz, 3H),0.50-0.40 (m, 4H).

3-(4-{3-[(Cyclopropyl-methyl-amino)-methyl]-phenylethynyl}-phenyl)-2-methyl-acrylicacid Compound 33

A solution of3-(4-{3-[(cyclopropyl-methyl-amino)-methyl]-phenylethynyl}-phenyl)-2-methyl-acrylicacid ethyl ester (Intermediate 94, 0.15 g, 0.4 mmol) in ethanol (3 mL)and tetrahydrofuran (3 mL) was treated with a 3M solution of potassiumhydroxide (1 mL, 3 mmol) and the resulting reaction mixture was stirredat ambient temperature for overnight. The reaction mixture wasconcentrated, neutralized with 5% aqueous hydrochloric acid andextracted with ethyl acetate. The organic phase was washed with waterand brine, dried over anhydrous sodium sulfate, filtered and evaporatedto a solid. The solid was subjected to flash column chromatography using5% methanol in ethyl acetate as the eluent to afford the title productas an amorphous solid (0.115 g, 83%).

¹H NMR (300 MHz, CDCl₃): δ 7.71-7.25 (m, 9H), 3.81 (s, 2H), 2.44 (s,3H), 2.13 (d, J=1.2 Hz, 3H), 1.92-1.80 (m, 1H), 0.76-0.66 (m, 2H),0.58-0.48 (m, 2H).

3-Bromo-N-cyclopropyl-4-methyl-benzamide Intermediate 95

A stirred, cooled (ice bath) solution of 3-bromo-4-methyl-benzoic acid(Aldrich, 5 g, 23.25 mmol) in benzene (50 mL), dichloromethane (10 mL)and N,N-dimethylformamide (0.5 mL) was treated with oxalyl chloride (4mL, 46.5 mmol). The reaction mixture was allowed to warm to ambienttemperature over 3 h. The volatiles were then distilled off in vacuo,the residue was diluted with anhydrous dichloromethane (50 mL) underargon, cooled (ice bath) and treated with 4-(dimethylamino)pyridine(5.67 g, 46.5 mmol) followed by cyclopropyl amine (1.93 mL, 27.9 mmol).After 3 h, the reaction mixture was diluted with dichloromethane andwashed with water. The organic phase was dried over anhydrous sodiumsulfate, filtered and evaporated in vacuo to afford the title productthat was used as such for the next step (6.0 g, ˜100%).

3-Bromo-N-cyclopropyl-4,N-dimethyl-benzamide Intermediate 96

A stirred, cooled (ice bath) solution of3-bromo-N-cyclopropyl-4-methyl-benzamide (Intermediate 95, 6 g, 23.25mmol) in anhydrous tetrahydrofuran (100 mL) under argon was treated withsmall portions of sodium hydride (1.6 g, 40 mmol, 60% dispersion inmineral oil). The reaction mixture was allowed to warm to ambienttemperature and after 1 h, methyl iodide (3.11 mL, 50 mmol) was addedand the reaction mixture was refluxed for 5 h. It was cooled to ambienttemperature, poured into cold water and extracted with diethyl ether(×2). The combined organic phase was dried over anhydrous magnesiumsulfate, filtered and evaporated in vacuo to afford the title product asa dirty brown solid that was used as such for the next step (6.3 g,˜100%).

(3-Bromo-4-methyl-benzyl)-cyclopropyl-methyl-amine Intermediate 97

A solution of 3-bromo-N-cyclopropyl-4,N-dimethyl-benzamide (Intermediate96, 5.3 g, 19.77 mmol) in anhydrous tetrahydrofuran (50 mL) was treatedwith borane-methyl sulfide complex (10 mL, 100 mmol) and the resultingreaction mixture was refluxed for 2 h. It was cooled to ambienttemperature and carefully treated with saturated, aqueous sodiumcarbonate solution till cessation of effervescence, and extracted withdiethyl ether (×2). The combined organic phase was dried over anhydrousmagnesium sulfate, filtered and evaporated in vacuo to an oil. Flashcolumn chromatography over silica gel (230-400 mesh) using 10% ethylacetate in hexane as the eluent afforded the title product as an oil(3.2 g, 63%).

¹H NMR (300 MHz, CDCl₃): δ 7.47 (s, 1H), 7.17 (d, 1H, J=7.8 Hz), 7.12(d, 1H, J=7.8 Hz), 3.63 (s, 2H), 2.40 (s, 3H), 2.27 (s, 3H), 1.73 (m,1H), 0.92-0.43 (m, 4H).

Cyclopropyl-methyl-(4-methyl-3-trimethylsilanylethynyl-benzyl)-amineIntermediate 98

Following General Procedure D and usingcyclopropyl-(3-bromo-4-methylbenzyl)-methyl-amine (Intermediate 97, 2.24g, 8.81 mmol), triethyl amine (10 mL), tetrahydrofuran (5 mL),copper(I)iodide (0.4 g, 2.1 mmol), trimethylsilyl acetylene (5 mL, 35.4mmol) and dichlorobis(triphenylphosphine)palladium(II) (1.45 g, 2.06mmol) followed by flash column chromatography over silica gel (230-400mesh) using 6-10% ethyl acetate in hexane as the eluent, the titlecompound (2.25 g, 94%) was obtained.

¹H NMR (300 MHz, CDCl₃): δ 7.08 (s, 1H), 6.84 (2s, 2H), 3.31 (s, 2H),2.15 (s, 3H), 1.95 (s, 3H), 1.41 (m, 1H), 0.25-0.00 (m, 4H), 0.00 (s,9H).

Cyclopropyl-(3-ethynyl-4-methyl-benzyl)-methyl-amine Intermediate 99

A solution ofcyclopropyl-methyl-(4-methyl-3-trimethylsilanylethynyl-benzyl)amine(Intermediate 98, 0.95 g, 3.5 mmol) in methanol (10 mL) was treated withpotassium carbonate (2.3 g, 16.6 mmol) and the resulting reactionmixture was stirred at ambient temperature for 1 h. The solvent wasevaporated in vacuo, the residue was diluted with water and extractedwith diethyl ether. The organic phase was washed with brine, dried overanhydrous magnesium sulfate, filtered and evaporated in vacuo to affordthe title compound (0.67 g, 96%).

¹H NMR (300 MHz, CDCl₃): δ 7.12 (s, 1H), 6.87 (2s, 2H), 3.33 (s, 2H),2.98 (s, 1H), 2.16 (s, 3H), 1.96 (s, 3H), 1.42 (m, 1H), 0.24-0.00 (m,4H).

(E)-3-(4-{5-[(Cyclopropyl-methyl-amino)-methyl]-2-methyl-phenylethynyl}-phenyl)-acrylicacid ethyl ester Intermediate 100

Following General Procedure B and usingcyclopropyl-(3-ethynyl-4-methylbenzyl)-methyl-amine (Intermediate 99,0.095 g, 0.48 mmol), ethyl-4-iodo-cinnamate (Reagent 3, 0.144 g, 0.47mmol), triethyl amine (13 mL), copper(I)iodide (0.019 g, 0.1 mmol) anddichlorobis(triphenylphosphine)palladium(II) (0.071 g, 0.1 mmol)followed by flash column chromatography over silica gel (230-400 mesh)using 5-20% ethyl acetate in hexane as the eluent, the title compoundwas obtained (0.14 g, 82%).

¹H NMR (300 MHz, CDCl₃): δ 7.66 (d, 1H, J=15.9 Hz), 7.53 (Abq, 4H, J=6.3Hz), 7.41 (s, 1H), 7.15 (2s, 2H), 6.44 (d, 1H, J=15.9 Hz), 4.26 (q, 2H,J=7.2 Hz), 3.62 (s, 2H), 2.48 (s, 3H), 2.24 (s, 3H), 1.68 (m, 1H), 1.33(t, 3H, J=7.2 Hz), 0.49-0.41 (m, 4H).

(E)-3-(4-{5-[(Cyclopropyl-methyl-amino)-methyl]-2-methyl-phenylethynyl}-phenyl)-acrylicacid Compound 34

A solution of(E)-3-(4-{5-[(cyclopropyl-methyl-amino)-methyl]-2-methyl-phenylethynyl}-phenyl)-acrylicacid ethyl ester (Intermediate 100, 0.14 g, 0.37 mmol) in ethanol (3 mL)and tetrahydrofuran (3 mL) was treated with a 3M solution of potassiumhydroxide (1 mL, 3 mmol) and the resulting reaction mixture was stirredat ambient temperature overnight. The reaction mixture was neutralizedwith 5% aqueous hydrochloric acid and extracted with ethyl acetate. Theorganic phase was washed with water and brine, and dried over anhydroussodium sulfate, filtered and evaporated in vacuo to a residue that wassubjected to flash column chromatography over silica gel (230-400 mesh)using 5% methanol in ethyl acetate as the eluent to afford the titleproduct as an amorphous solid (0.071 g, 55%).

¹H NMR (300 MHz, CDCl₃): δ 7.62 (d, 1H, J=15.9 Hz), 7.61 (s, 1H), 7.38(s, 4H), 7.19 (s, 2H), 6.56 (d, 1H, J=15.9 Hz), 3.87 (s, 2H), 2.50 (s,3H), 2.49 (s, 3H), 1.94 (m, 1H), 0.89-0.83 (m, 2H), 0.60-0.57 (m, 2H).

Trifluoro-methanesulfonic acid 3-tert-butyl-phenyl ester Intermediate101

A stirred, cooled (ice bath) solution of 3-tert-butyl phenol (Aldrich, 2g, 13.3 mmol) in anhydrous dichloromethane (15 mL) was treated with2-[N,N′-bis(trifluoromethylsulfonyl)amino]-5-chloropyridine (7.8 g, 20mmol) followed by 4-(dimethylamino)pyridine (3.2 g, 26.6 mmol). Thecooling bath was removed and the reaction mixture was stirred at ambienttemperature for 18 h. It was diluted with ethyl acetate, washed with 2Nhydrochloric acid, 2N sodium hydroxide, and brine, dried over anhydrousmagnesium sulfate, filtered and evaporated in vacuo to an oil. Flashcolumn chromatography over silica gel (230-400 mesh) using 10% ethylacetate in hexane as the eluent afforded the title product as a clearoil (3.06 g, 82%). ¹H NMR (300 MHz, CDCl₃): δ 7.42-7.32 (m, 2H), 7.24(d, 1H, J=1.8 Hz), 7.10-7.06 (m, 1H), 1.33 (s, 9H).

(3-tert-Butyl-phenylethynyl)-trimethyl-silane Intermediate 102

Following General Procedure D and using trifluoromethanesulfonic acid,3-tertbutyl-phenyl ester (Intermediate 101, 2.54 g, 9.0 mmol), triethylamine (2 mL), copper(I)iodide (0.63 g, 3.33 mmol), trimethylsilylacetylene (5 mL, 36 mmol) anddichlorobis(triphenylphosphine)palladium(II) (1.6 g, 2.25 mmol) followedby flash column chromatography over silica gel (230-400 mesh) using 10%ethyl acetate in hexane as the eluent, the title compound was obtainedas a brown oil that was used as such for the next step.

1-tert-Butyl-3-ethynyl-benzene Intermediate 103

A solution 3-tert-butyl-trimethylsilanylethynyl benzene (Intermediate102, 0.47 g, 2.04 mmol) in methanol (20 mL) was treated with potassiumcarbonate (2.8 g, 20.2 mmol) and the resulting reaction mixture wasstirred at ambient temperature for 3 days. The reaction mixture wasdiluted with ethyl acetate, washed with water and brine, dried overanhydrous magnesium sulfate, filtered and evaporated in vacuo to an oil.Flash column chromatography over silica gel (230-400 mesh) using 10%ethyl acetate in hexane as the eluent afforded the title compound as alight yellow oil (0.125 g, 39%).

¹H NMR (300 MHz, CDCl₃): δ 7.40 (d, 1H, J=1.5 Hz), 7.39-7.10 (m, 3H),2.91 (s, 1H), 1.18 (s, 9H).

(E)-3-[4-(3-tert-Butyl-phenylethynyl)-phenyl]-acrylic acid Compound 35

A solution of (E)-3-[4-(3-tert-butyl-phenylethynyl)-phenyl]-acrylic acidethyl ester (Intermediate 103, 0.015 g, 0.047 mmol) in ethanol (2 mL)and tetrahydrofuran (2 mL) was treated with a 2M solution of lithiumhydroxide (1 mL, 2 mmol) and the resulting reaction mixture was stirredat ambient temperature overnight. The reaction mixture was neutralizedwith 10% aqueous hydrochloric acid and evaporated in vacuo to a solidthat was washed with water and hexane and dried to afford the titleproduct as a white solid (0.012 g, 85%). ¹H NMR (300 MHz, CDCl₃): δ 7.78(d, 1H, J=16.2 Hz), 7.59-7.26 (m, 8H), 6.47 (d, 1H, J=16.2 Hz), 1.34 (s,9H).

4-tert-Butyl-2-hydroxy-benzaldehyde Intermediate 104

A stirred, cooled (ice bath) solution of 3-tert-butyl phenol (1.5 g, 10mmol) in anhydrous dichloromethane was treated with titaniumtetrachloride (1.86 mL, 17 mmol) followed by ∀,∀-dichloromethyl ether(0.9 mL, 20 mmol). The reaction was allowed to warm to ambienttemperature over 1 h, quenched cautiously with ice and water andextracted with dichloromethane. The organic extract was washed withwater and brine, dried over sodium sulfate, filtered and evaporated invacuo to a residue that was subjected to flash column chromatographyusing 2-2.5% ethyl acetate in hexane as the eluent to afford the titlecompound (1.37 g, 77%). ¹H NMR (300 MHz, CDCl₃): δ 11.02 (s, 1H), 9.81(s, 1H), 7.45 (d, J=8.2 Hz, 1H), 7.03 (dd, J=8.2, 1.7 Hz, 1H), 6.99 (d,J=1.7 Hz, 1H), 1.31 (s, 9H).

Trifluoro-methanesulfonic acid 5-tert-butyl-2-formyl-phenyl esterIntermediate 105

A stirred, cooled (ice-bath) solution of4-tert-butyl-2-hydroxy-benzaldehyde (Intermediate 104, 0.75 g, 4.21mmol) in anhydrous dichloromethane (10 mL) was treated with triethylamine (1.76 mL, 12.64 mmol) followed by2-[N,N-bis(trifluoromethylsulfonyl)amino]pyridine (1.81 g, 4.62 mmol).The reaction mixture was allowed to warm to ambient temperatureovernight. The volatiles were evaporated and the residue was subjectedto flash column chromatography using 2-2.5% ethyl acetate in hexane asthe eluent to afford the title compound (0.16 g) and a 1:1 mixture ofproduct and starting material (0.47 g). The title compound was used assuch for the next step.

5-tert-Butyl-2-hydroxymethyl-phenol Intermediate 106

A stirred, cooled (ice-bath) solution of a 1:1 mixture oftrifluoro-methanesulfonic acid 5-tert-butyl-2-formyl-phenyl ester and4-tert-butyl-2-hydroxy-benzaldehyde (Intermediate 105, 0.47 g) inmethanol (8 mL) was treated with sodium borohydride (0.1 g, 2.64 mmol).After 1 h, the reaction mixture was diluted with water and extractedwith ethyl acetate. The organic phase was washed with water and brine,dried over anhydrous sodium sulfate, filtered and evaporated in vacuo toa residue that was subjected to flash column chromatography on silicagel (230-400 mesh) to afford the title product (0.3 g).

¹H NMR (300 MHz, CDCl₃): δ 6.94-6.84 (m, 3H), 4.72 (s, 2H), 1.26 (s,9H).

5-tert-Butyl-2-methyl-phenol Intermediate 107

A solution of 5-tert-butyl-2-hydroxymethyl-phenol (Intermediate 106,0.215 g, 1.19 mmol) in ethyl acetate was treated with 5% palladium oncarbon (0.04 g) and the resulting reaction mixture was stirred under anatmosphere of hydrogen at ambient temperature for 2.5 h. The reactionmixture was then filtered over a bed of celite and the filtrate wasevaporated in vacuo to afford the title compound as a white solid (0.19g, 97%).

¹H NMR (300 MHz, CDCl₃): δ 7.03 (d, J=7.9 Hz, 1H), 6.86 (dd, J=7.9, 1.7Hz, 1H), 6.78 (d, 1=1.7 Hz, 1H), 5.20 (s, 1H), 2.20 (s, 3H), 1.25 (s,9H).

Trifluoro-methanesulfonic acid 5-tert-butyl-2-methyl-phenyl esterIntermediate 108

A solution of 5-tert-butyl-2-methyl-phenol (Intermediate 107, 0.19 g,1.15 mmol) and 4-(dimethylamino)pyridine (0.28 g, 2.3 mmol) in anhydrousdichloromethane (8 mL) was treated withN-phenyltrifluoromethanesulfonimide (0.54 g, 1.5 mmol), and theresulting reaction mixture was stirred at ambient temperature overnight.The reaction mixture was concentrated in vacuo and the residue wassubjected to flash column chromatography over silica gel (230-400 mesh)to afford the title compound as a colorless oil (0.28 g, 82%).

¹H NMR (300 MHz, CDCl₃): δ 7.30-7.20 (m, 3H), 2.33 (s, 3H), 1.30 (s,9H).

(5-tert-Butyl-2-methyl-phenylethynyl)-trimethyl-silane Intermediate 109

Following General Procedure D and using trifluoro-methanesulfonic acid5-tert-butyl-2-methyl-phenyl ester (Intermediate 108, 0.28 g, 0.94mmol), triethyl amine (3 mL), trimethylsilyl acetylene (1 mL, 7 mmol),N,N-dimethylformamide (6 mL) anddichlorobis(triphenylphosphine)palladium(II) (0.053 g, 0.076 mmol)followed by flash column chromatography over silica gel (230-400 mesh)using hexane as the eluent, the title compound (0.16 g, 69%) wasobtained. ¹H NMR (300 MHz, CDCl₃): δ 7.44 (d, J=1.7 Hz, 1H), 7.22 (dd,J=8.2, 1.7 Hz, 1H), 7.10 (d, J=8.2 Hz, 1H), 2.39 (s, 3H), 1.28 (s, 9H),0.26 (s, 9H).

4-tert-Butyl-2-ethynyl-1-methyl-benzene Intermediate 110

Following general procedure F and using(5-tert-butyl-2-methyl-phenylethynyl)trimethyl-silane (Intermediate 109,0.16 g, 0.66 mmol), methanol (5 mL) and potassium carbonate (0.05 g,0.36 mmol), the title compound was obtained (0.08 g, 67%).

¹H NMR (300 MHz, CDCl₃): δ 7.49 (d, J=1.7 Hz, 1H), 7.30 (dd, J=8.2, 1.7Hz, 1H), 7.15 (d, J=8.2 Hz, 1H), 3.16 (s, 1H), 2.42 (s, 3H), 1.32 (s,9H).

3-[4-(5-tert-Butyl-2-methyl-phenylethynyl)-phenyl]-acrylic acid ethylester Intermediate 111

Following General Procedure B and using4-tert-butyl-2-ethynyl-1-methyl-benzene (Intermediate 110, 0.08 g, 0.47mmol), ethyl-4-iodocinnamate (0.12 g, 0.4 mmol), triethyl amine (8 mL),copper(I)iodide (0.019 g, 0.1 mmol) anddichlorobis(triphenylphosphine)palladium(II) (0.07 g, 0.1 mmol) followedby flash column chromatography over silica gel (230-400 mesh) using 2-4%ethyl acetate in hexane as the eluent, the title compound was obtained(0.09 g, 55%).

¹H NMR (300 MHz, CDCl₃): δ 7.67 (d, J=16.1 Hz, 1H), 7.56-7.48 (m, 5H),7.28 (dd, J=8.2, 1.7 Hz, 1H), 7.16 (d, J=8.2 Hz, 1H), 6.44 (d, J=16.1Hz, 1H), 4.27 (q, J=7.1 Hz, 2H), 2.48 (s, 3H), 1.33 (t, J=7.1 Hz, 3H),1.32 (s, 9H).

3-[4-(5-tert-Butyl-2-methyl-phenylethynyl)-phenyl]-acrylic acid Compound36

A solution of 3-[4-(5-tert-butyl-2-methyl-phenylethynyl)-phenyl]-acrylicacid ethyl ester (Intermediate 111, 0.09 g, 0.26 mmol) in ethanol (3 mL)and tetrahydrofuran (3 mL) was treated with 3M potassium hydroxidesolution (1 mL, 3 mmol) and the resulting reaction mixture was stirredovernight at ambient temperature. The reaction mixture was concentratedin vacuo slightly, the residue was neutralized with dilute hydrochloricacid, and the solid that was formed was filtered and washed with waterand acetonitrile and dried to afford title product (0.064 g, 77%).

¹H NMR (300 MHz, CDCl₃): δ 7.78 (d, J=16.1 Hz, 1H), 7.58-7.53 (m, 5H),7.29 (dd, J=7.9, 1.7 Hz, 1H), 7.17 (d, J=7.9 Hz, 1H), 6.47 (d, J=16.1Hz, 1H), 2.48 (s, 3H), 1.32 (s, 9H).

N-(3-Bromo-phenyl)-N-methyl-formamide Intermediate 112

A solution of 3-bromo-N-methyl aniline (made as described by Lopez etal. in Tet. Lett., 1999, 40, 11, p 2071-2074 incorporated herein byreference; 7.4 g, 39.5 mmol) in formic acid (20 mL) was refluxed for 3h. The reaction mixture was then cooled to ambient temperature, dilutedwith water and extracted with diethyl ether. The organic phase waswashed with saturated, aqueous sodium bicarbonate solution, water andbrine, dried over anhydrous magnesium sulfate, filtered and evaporatedin vacuo to afford the title product as a dark brown oil.

(3-Bromo-phenyl)-cyclopropyl-methyl-amine Intermediate 113

A stirred, cooled (0° C.) solution ofN-(3-bromo-phenyl)-N-methyl-formamide (Intermediate 112, 2.6 g, 9.7mmol) and titanium tetra-iso-propoxide (3.9 mL, 10.67 mmol) intetrahydrofuran (40 mL) was treated with a 3M solution of ethylmagnesium bromide in ether (8.08 mL, 24.25 mmol) under argon and theresulting reaction mixture was allowed to warm to ambient temperaturegradually and refluxed at 55° C. overnight. It was then cooled in anice-bath, quenched with saturated aqueous ammonium chloride solution,filtered over celite and the aqueous phase was extracted with diethylether. The organic phase was dried over anhydrous magnesium sulfate,filtered and evaporated in vacuo to afford an oil. Flash columnchromatography over silica gel (230-400 mesh) using 1.5% ethyl acetatein hexane as the eluent afforded the title compound (0.321 g, 15%).

Cyclopropyl-methyl-(3-trimethylsilanylethynyl-phenyl)-amine Intermediate114

Following General Procedure D and using(3-bromo-phenyl)-cyclopropyl-methyl-amine (Intermediate 113, 0.056 g,0.25 mmol), triethyl amine (3 mL), copper(I)iodide (0.025 g, 0.13 mmol),trimethylsilyl acetylene (2.5 mL, 17.6 mmol) anddichlorobis(triphenylphosphine)palladium(II) (0.065 g, 0.09 mmol)followed by flash column chromatography over silica gel (230-400 mesh)using 1.5% ethyl acetate in hexane as the eluent, the title compound(0.051 g, 84%) was obtained.

Cyclopropyl-(3-ethynyl-phenyl)-methyl-amine Intermediate 115

A solution ofcyclopropyl-methyl-(3-trimethylsilanylethynyl-phenyl)-amine(Intermediate 114, 0.05 g, 0.2 mmol) in methanol (5 mL) was treated withpotassium carbonate (0.063 g, 0.46 mmol) and the resulting reactionmixture was heated at 80° C. for 3 h. The solvent was evaporated invacuo, the residue was diluted with water and extracted with diethylether. The organic phase was dried over anhydrous magnesium sulfate,filtered and evaporated in vacuo to afford the title compound (0.035 g,100%).

(E)-3-{4-[3-(Cyclopropyl-methyl-amino)-phenylethynyl}-acrylic acid ethylester Intermediate 116

Following General Procedure B and usingcyclopropyl-(3-ethynyl-phenyl)methyl-amine (Intermediate 115, 0.035 g,0.2 mmol), ethyl-4-iodo-cinnamate (0.082 g, 0.27 mmol), triethyl amine(3 mL), copper(I)iodide (0.025 g, 0.13 mmol) anddichlorobis(triphenylphosphine)palladium(II) (0.033 g, 0.047 mmol)followed by flash column chromatography over silica gel (230-400 mesh),and preparative normal phase HPLC using 10% ethyl acetate in hexane asthe mobile phase, the title compound was obtained (0.020 g, 29%).

(E)-3-{4-[3-(Cyclopropyl-methyl-amino)-phenylethynyl]-phenyl}-acrylicacid Compound 37

A solution of(E)-3-{4-[3-(cyclopropyl-methyl-amino)-phenylethynyl}-acrylic acid ethylester (Intermediate 116, 0.020 g, 0.057 mmol) in ethanol (1 mL) wastreated with a 1M solution of sodium hydroxide (1 mL, 1 mmol) and theresulting reaction mixture was heated at 80° C. for 30 minutes. Thevolatiles were evaporated in vacuo to a residue that was neutralizedwith saturated aqueous ammonium chloride solution and extracted withethyl acetate. The organic phase was dried over anhydrous magnesiumsulfate, filtered and evaporated in vacuo to afford a residue that onpreparative reverse phase HPLC using 10% water in acetonitrile as themobile phase afforded the title product as a yellow solid (0.006 g,33%).

4-Bromo-2-methyl-benzoic acid isopropyl ester Intermediate 117

A solution of 4-bromo-2-methyl-benzoic acid (Aldrich, 5.4 g, 25 mmol) inbenzene (75 mL) and isopropanol (75 mL) was treated with concentratedsulfuric acid (1.5 mL) and heated to reflux over 4 days using aDean-Stark water trap. The volatiles were evaporated in vacuo, theresidue was diluted with water and extracted with diethyl ether. Theorganic phase was washed with water and saturated, aqueous sodiumbicarbonate solution, dried over anhydrous magnesium sulfate, filteredand evaporated in vacuo to afford the title product as a clear oil thatwas used as such for the next step (6.12 g, 95%).

4-Bromo-2-bromomethyl-benzoic acid isopropyl ester Intermediate 118

A solution of 4-bromo-2-methyl-benzoic acid isopropyl ester(Intermediate 117, 6.12 g, 23.8 mmol) in carbon tetrachloride (120 mL)was treated with N-bromosuccinimide (4.6 g, 26.18 mmol) and2,2′-azobisisobutyronitrile (0.6 g) and the resulting reaction mixturewas refluxed overnight. It was cooled to ambient temperature, the solidswere filtered off and washed with 1:1 hexane:diethyl ether, and thefiltrate and washings were evaporated in vacuo to afford an oil (5.1 g,64%) that was used as such for the next step.

4-Bromo-2-cyclopropylaminomethyl-benzoic acid isopropyl esterIntermediate 119

A stirred, cooled (ice bath) solution of 4-bromo-2-bromomethyl-benzoicacid isopropyl ester (Intermediate 118, 5.1 g, 15.17 mmol) inacetonitrile (25 mL) was treated with cyclopropyl amine (2 mL, 28.9mmol). The reaction mixture was allowed to warm to ambient temperature.After 2 h, the volatiles were evaporated in vacuo, the residue wasdiluted with water and extracted with diethyl ether (×2). The combinedorganic phase was dried over anhydrous magnesium sulfate, filtered andevaporated in vacuo to an oil. Flash column chromatography over silicagel (230-400 mesh) using 4-20% ethyl acetate in hexane as the eluent toafforded the title product (1.33 g, 28%).

¹H NMR (300 MHz, CDCl₃): δ 7.73 (d, 1H, J=8.4 Hz), 7.56 (d, 1H, J=2.1Hz), 7.41 (dd, 1H, J=2.1, 8.4 Hz), 5.21 (heptet, 1H, J=6.3 Hz), 4.00 (s,2H), 2.39 (br s, 1H), 2.06 (m, 1H), 1.35 (d, 6H, J=6.3 Hz), 0.42-0.34(m, 4H).

4-Bromo-2-[(cyclopropyl-methyl-amino)-methyl]-benzoic acid isopropylester Intermediate 120

A solution of 4-bromo-2-cyclopropylaminomethyl-benzoic acid isopropylester (Intermediate 119, 1.33 g, 4.26 mmol) in acetone (8 mL) wastreated with potassium carbonate (2.36 g, 17.05 mmol) and methyl iodide(0.53 mL, 8.52 mmol) and the resulting reaction mixture was stirred atambient temperature for 3 h. The volatiles were evaporated in vacuo, theresidue was diluted with water and extracted with diethyl ether (×2).The combined organic phase was dried over anhydrous magnesium sulfate,filtered over a short bed of silica gel (230-400 mesh) and evaporated invacuo to afford the title product (1.23 g, 70%).

¹H NMR (300 MHz, CDCl₃): δ 7.64 (d, 1H, J=2.1 Hz), 7.58 (d, 1H, J=8.4Hz), 7.39 (dd, 1H, J=2.1, 8.4 Hz), 5.20 (heptet, 1H, J=6.0 Hz), 3.97 (s,2H), 2.22 (s, 3H), 1.77 (m, 1H), 1.35 (d, 6H, J=6.0 Hz), 0.46-0.38 (m,4H).

2-[(Cyclopropyl-methyl-amino)-methyl]-4-trimethylsilanylethynyl-benzoicacid isopropyl ester Intermediate 121

Following General Procedure D and using4-bromo-2-[(cyclopropyl-methylamino)-methyl]-benzoic acid isopropylester (Intermediate 120, 1.23 g, 3.68 mmol), triethyl amine (10 mL),tetrahydrofuran (5 mL), copper(I)iodide (0.21 g, 1.1 mmol),trimethylsilyl acetylene (2.1 mL, 14.7 mmol) anddichlorobis(triphenylphosphine)palladium(II) (0.77 g, 1.1 mmol) followedby flash column chromatography over silica gel (230-400 mesh) using 7%ethyl acetate in hexane as the eluent, the title compound was obtainedas an oil (1.2 g, ˜100%).

¹H NMR (300 MHz, CDCl₃): δ 7.62 (d, 1H, J=8.1 Hz), 7.53 (s, 1H), 7.35(d, 1H, J=8.4 Hz), 5.20 (heptet, 1H, J=6.3 Hz), 3.95 (s, 2H), 2.22 (s,3H), 1.74 (m, 1H), 1.36 (d, 6H, J=6.3 Hz), 0.37-0.28 (m, 4H), 0.27 (s,9H).

2-[(Cyclopropyl-methyl-amino)-methyl]-4-ethynyl-benzoic acid isopropylester Intermediate 122

A solution2-[(cyclopropyl-methyl-amino)-methyl]-4-trimethylsilanylethynyl-benzoicacid isopropyl ester (Intermediate 121, 0.34 g, 1 mmol) in methanol (2mL) was treated with potassium carbonate (0.207 g, 1.5 mmol) and theresulting reaction mixture was stirred at ambient temperature for 4 h.The volatiles were evaporated in vacuo, the residue was diluted withwater and extracted with diethyl ether, dried over anhydrous magnesiumsulfate, filtered and evaporated in vacuo to afford the title compoundas an oil (0.21 g, 78%).

¹H NMR (300 MHz, CDCl₃): δ 7.67 (d, 1H, J=7.8 Hz), 7.64 (d, 1H, J=1.8Hz), 7.38 (dd, 1H, J=1.8, 7.8 Hz), 5.21 (heptet, 1H, J=6.0 Hz), 3.96 (s,2H), 3.16 (s, 1H), 2.22 (s, 3H), 1.74 (m, 1H), 1.36 (d, 6H, J=6.0 Hz),0.44-0.33 (m, 4H).

2-[(Cyclopropyl-methyl-amino)-methyl]-4-(4-methoxycarbonylmethyl-phenylethynyl)benzoicacid isopropyl ester Intermediate 123

Following General Procedure B and using2-[(cyclopropyl-methyl-amino)methyl]-4-ethynyl-benzoic acid isopropylester (Intermediate 122, 0.09 g, 0.33 mmol), 4-iodophenyl acetic acidmethyl ester (0.09 g, 0.33 mmol), triethyl amine (2 mL), copper(I)iodide(0.04 g, 0.21 mmol) and dichlorobis(triphenylphosphine)palladium(II)(0.1 g, 0.14 mmol) followed by flash column chromatography over silicagel (230-400 mesh) using 10-15% ethyl acetate in hexane as the eluent,the title compound was obtained as an oil. (0.1 g, 72%).

¹H NMR (300 MHz, CDCl₃): δ 7.70 (d, 1H, J=7.8 Hz), 7.62 (d, 1H, J=1.8Hz), 7.52 (d, 2H, J=8.1 Hz), 7.43 (dd, 1H, J=1.8, 7.8 Hz), 7.28 (d, 2H,J=8.1 Hz), 5.25 (heptet, 1H, J=6.0 Hz), 4.00 (s, 2H), 3.71 (s, 3H), 3.65(s, 2H), 2.26 (s, 3H), 1.78 (m, 14H), 1.38 (d, 6H, J=6.0 Hz), 0.44-0.40(m, 4H).

4-(4-Carboxymethyl-phenylethynyl)-2-[(cyclopropyl-methyl-amino)-methyl]-benzoicacid isopropyl ester Compound 38

A solution of2-[(cyclopropyl-methyl-amino)-methyl]-4-(4-methoxycarbonylmethyl-phenylethynyl)-benzoicacid isopropyl ester (Intermediate 123, 0.1 g, 0.23 mmol) in a mixtureof methanol (2 mL), tetrahydrofuran (2 mL) and water (1 mL) was treatedwith lithium hydroxide monohydrate (0.042 g, 1 mmol) and the resultingreaction mixture was stirred at ambient temperature for 2 h. Thevolatiles were evaporated in vacuo, the residue was neutralized withsaturated, aqueous ammonium chloride solution and extracted with ethylacetate. The combined organic extract was dried over anhydrous magnesiumsulfate, filtered and evaporated in vacuo to a solid. Preparativereverse phase HPLC using 10% water in acetonitrile as the mobile phaseafforded the title product as a white solid (0.068 g, 72%). ¹H NMR (300MHz, CDCl₃): δ 9.05 (br s, 1H), 7.73 (d, 1H, J=8.4 Hz), 7.66 (s, 1H),7.44-7.37 (m, 3H), 7.23-7.21 (m, 2H), 5.20 (heptet, 1H, J=6.0 Hz), 4.21(s, 2H), 3.52 (s, 2H), 2.36 (s, 3H), 1.94 (m, 1H), 1.36 (d, 6H, J=6.0Hz), 0.55-0.43 (m, 4H).

2-[(Cyclopropyl-methyl-amino)-methyl]-4-(3-fluoro-4-methoxycarbonylmethyl-phenylethynyl)-benzoicacid isopropyl ester Intermediate 124

Following General Procedure B and using2-[(cyclopropyl-methyl-amino)methyl]-4-ethynyl-benzoic acid isopropylester (Intermediate 122, 0.05 g, 0.18 mmol), 2-fluoro-4-iodophenylacetic acid methyl ester (0.07 g, 0.24 mmol), triethyl amine (2mL), copper(I)iodide (0.04 g, 0.21 mmol) anddichlorobis(triphenylphosphine)palladium(II) (0.07 g, 0.1 mmol) followedby flash column chromatography over silica gel (230-400 mesh) using15-16% ethyl acetate in hexane as the eluent, the title compound wasobtained as an oil (0.04 g, 50%).

¹H NMR (300 MHz, CDCl₃): δ 7.63 (d, 1H, J=7.8 Hz), 7.55 (d, 1H, J=1.2Hz), 7.35 (dd, 1H, J=1.2, 7.8 Hz), 7.26-7.17 (m, 3H), 5.16 (heptet, 1H,J=6.3 Hz), 3.93 (s, 2H), 3.66 (s, 3H), 3.64 (s, 2H), 2.20 (s, 3H), 1.71(m, 1H), 1.31 (d, 6H, J=6.3 Hz), 0.40-0.33 (m, 4H).

4-(4-Carboxymethyl-3-fluoro-phenylethynyl)-2-[(cyclopropyl-methyl-amino)-methyl]-benzoicacid isopropyl ester Compound 39

A solution of2-[(cyclopropyl-methyl-amino)-methyl]-4-(3-fluoro-4-methoxycarbonylmethyl-phenylethynyl)-benzoicacid isopropyl ester (Intermediate 124, 0.04 g, 0.09 mmol) in a mixtureof methanol (2 mL), tetrahydrofuran (2 mL) and water (1 mL) was treatedwith lithium hydroxide monohydrate (0.042 g, 1 mmol) and the resultingreaction mixture was stirred at ambient temperature for 2 h. Thevolatiles were evaporated in vacuo, the residue was neutralized withsaturated, aqueous ammonium chloride solution and extracted with ethylacetate. The combined organic extract was dried over anhydrous magnesiumsulfate, filtered and evaporated in vacuo to a solid. Preparativereverse phase HPLC using 10% water in acetonitrile as the mobile phaseafforded the title product as a white solid (0.026 g, 54%). ¹H NMR (300MHz, CDCl₃): δ 7.71 (d, 1H, J=8.1 Hz), 7.64 (s, 1H), 7.41 (d, 1H, J=8.1Hz), 7.17-7.09 (m, 3H), 5.20 (heptet, 1H, J=6.3 Hz), 4.16 (s, 2H), 3.54(s, 2H), 2.34 (s, 3H), 1.91 (m, 1H), 1.36 (d, 6H, J=6.3 Hz), 0.50-0.41(m, 4H).

2-[(Cyclopropyl-methyl-amino)-methyl]-4-(4-methoxycarbonylmethyl-phenylethynyl)benzoicacid isopropyl ester Intermediate 125

Following General Procedure B and using2-[(cyclopropyl-methyl-amino)methyl]-4-ethynyl-benzoic acid isopropylester (Intermediate 122, 0.07 g, 0.26 mmol),methyl-2-(4-iodophenyl)-propionate (Reagent 1, 0.081 g, 0.29 mmol),triethyl amine (2 mL), copper(I)iodide (0.03 g, 0.158 mmol) anddichlorobis(triphenylphosphine)palladium(II) (0.07 g, 0.1 mmol) followedby flash column chromatography over silica gel (230-400 mesh) using10-15% ethyl acetate in hexane as the eluent, the title compound wasobtained as an oil (0.09 g, 81%).

¹H NMR (300 MHz, CDCl₃): δ 7.57 (d, 1H, J=8.1 Hz), 7.49 (d, 1H, J=1.8Hz), 7.39 (d, 2H, J=8.4 Hz), 7.30 (dd, 1H, J=1.8, 8.1 Hz), 7.18 (d, 2H,J=8.4 Hz), 5.10 (heptet, 1H, J=6.0 Hz), 3.88 (s, 2H), 3.63 (q, 1H, J=7.2Hz), 3.56 (s, 3H), 2.13 (s, 3H), 1.65 (m, 1H), 1.40 (d, 3H, J=7.2 Hz),1.25 (d, 6H, J=6.0 Hz), 0.35-0.27 (m, 4H).

4-[4-(1-Carboxy-ethyl)-phenylethynyl]-2-[(cyclopropyl-methyl-amino)-methyl]-benzoicacid isopropyl ester Compound 40

A solution of2-[(cyclopropyl-methyl-amino)-methyl]-4-(4-methoxycarbonylmethyl-phenylethynyl)-benzoicacid isopropyl ester (Intermediate 125, 0.09 g, 0.21 mmol) in a mixtureof methanol (2 mL), tetrahydrofuran (2 mL) and water (1 mL) was treatedwith lithium hydroxide monohydrate (0.042 g, 1 mmol) and the resultingreaction mixture was stirred at ambient temperature for 4 h. Thevolatiles were evaporated in vacuo, the residue was neutralized withsaturated, aqueous ammonium chloride solution and extracted with ethylacetate. The combined organic extract was dried over anhydrous magnesiumsulfate, filtered and evaporated in vacuo to afford the title product asa white solid foam (0.053 g, 61%).

¹H NMR (300 MHz, CDCl₃): δ7.68 (d, 1H, J=8.1 Hz), 7.58 (d, 1H, J=1.8Hz), 7.44-7.25 (m, 5H), 5.13 (heptet, 1H, J=6.0 Hz), 4.18 (s, 2H), 3.79(m, 1H), 2.32 (s, 3H), 1.89 (m, 1H), 1.39 (d, 3H, J=6.6 Hz), 1.28 (d,6H, J=6.3 Hz), 0.52-0.21 (m, 4H).

4,4-Dimethyl-8-(2-propoxy)-6-trimethylsilanylethynyl-3,4-dihydro-2H-naphthalen-1-oneIntermediate 126

A solution of8-hydroxy-4,4-dimethyl-6-trimethylsilanylethynyl-3,4-dihydro-2H-naphthalen-1-one(Intermediate 66, 0.32 g, 1.12 mmol) in acetone (20 mL) was treated withpotassium carbonate (0.773 g, 5.6 mmol) and 2-iodopropane (2 g, 11.76mmol) and the resulting reaction mixture was refluxed for 3 days. It wascooled to ambient temperature, the solids were filtered off and thefiltrate was evaporated in vacuo to an oil that was subjected to flashcolumn chromatography over silica gel (230-400 mesh) using 2-6% ethylacetate in hexane as the eluent to afford the title product as (0.055 g,15%).

¹H NMR (300 MHz, CDCl₃): δ 7.04 (d, 1H, J=1.2 Hz), 6.89 (d, 1H, J=1.2Hz), 4.57 (heptet, 1H, J=6.3 Hz), 2.66 (t, 2H, J=7.2 Hz), 1.92 (t, 2H,J=7.2 Hz), 1.38 (d, 6H, J=6.3 Hz), 1.33 (s, 6H), 0.27 (s, 9H).

4,4-Dimethyl-6-ethynyl-8-(2-propoxy)-3,4-dihydro-2H-naphthalen-1-oneIntermediate 127

A solution4,4-dimethyl-8-(2-propoxy)-6-trimethylsilanylethynyl-3,4-dihydro-2H-naphthalen-1-one(Intermediate 126, 0.055 g, 0.167 mmol) in methanol (5 mL) was treatedwith potassium carbonate (0.03 g, 0.22 mmol) and the resulting reactionmixture was stirred at ambient temperature overnight. The solvent wasevaporated in vacuo, the residue was diluted with water and extractedwith ethyl acetate. The organic phase was washed with brine, dried overanhydrous magnesium sulfate, filtered and evaporated in vacuo to affordthe title compound (0.042 g, 98%).

¹H NMR (300 MHz, CDCl₃): δ 7.08 (d, 1H, J=1.2 Hz), 6.93 (d, 1H, J=1.2Hz), 4.56 (heptet, 1H, J=6.0 Hz), 3.19 (s, 1H), 2.67 (t, 2H, J=6.9 Hz),1.93 (t, 2H, J=6.9 Hz), 1.39 (d, 6H, J=6.0 Hz), 1.34 (s, 6H).

{4-[8,8-Dimethyl-5-oxo-4-(2-propoxy)-5,6,7,8-tetrahydro-naphthalen-2-ylethynyl]-phenyl}-aceticacid methyl ester Intermediate 128

Following General Procedure B and using4,4-dimethyl-6-ethynyl-8-(2-propoxy)-3,4-dihydro-2H-naphthalen-1-one(Intermediate 127, 0.075 g, 0.29 mmol), 4-iodo phenyl acetic acid methylester (0.081 g, 0.29 mmol), triethyl amine (8 mL), tetrahydrofuran (3mL), copper(I)iodide (0.019 g, 0.1 mmol) anddichlorobis(triphenylphosphine)palladium(II) (0.07 g, 0.1 mmol) followedby flash column chromatography over silica gel (230-400 mesh) using5-15% ethyl acetate in hexane as the eluent, the title compound wasobtained as a yellow oil (0.07 g, 64%).

¹H NMR (300 MHz, CDCl₃): δ 7.52 (d, 2H, J=8.4 Hz), 7.29 (d, 2H, J=8.4Hz), 7.12 (d, 1H, J=1.5 Hz), 6.97 (d, 1H, J=1.5 Hz), 4.60 (heptet, 1H,J=5.8 Hz), 3.71 (s, 3H), 3.66 (s, 2H), 2.68 (t, 2H, J=6.6 Hz), 1.95 (t,2H, J=6.6 Hz), 1.41 (d, 6H, J=5.8 Hz), 1.36 (s, 6H).

{4-[5-(Cyclopropyl-methyl-amino)-4-isopropoxy-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-ylethynyl]-phenyl}-aceticacid methyl ester Intermediate 129

A solution of{4-[8,8-dimethyl-5-oxo-4-(2-propoxy)-5,6,7,8-tetrahydro-naphthalen-2-ylethynyl]-phenyl}-aceticacid methyl ester (Intermediate 128, 0.07 g, 0.187 mmol) indichloromethane (3 mL) and acetonitrile (1.5 mL) was treated withcyclopropyl amine (1 mL, 14.45 mmol). After 5 minutes, acetic acid (1mL) was added followed by sodium cyanoborohydride (0.12 g, 1.91 mmol).The reaction mixture was stirred overnight at ambient temperature. Itwas then diluted with water and saturated aqueous sodium carbonatesolution and extracted with dichloromethane (×2). The combined organicextract was dried over anhydrous sodium sulfate, filtered and evaporatedin vacuo to an oil. The oil was dissolved in acetone (15 mL) and treatedwith potassium carbonate (0.2 g, 1.45 mmol) followed by methyl iodide (1mL, 15.8 mmol) and the resulting reaction mixture was stirred overnightat ambient temperature. The precipitated solids were filtered off, thefiltrate was evaporated in vacuo to a residue. Flash columnchromatography over silica gel (230-400 mesh) using 2.5-6% ethyl acetatein hexane as the eluent afforded the title compound (0.045 g, 53%).

¹H NMR (300 MHz, CDCl₃): δ 7.50 (d, 2H, J=8.4 Hz), 7.26 (d, 2H, J=8.4Hz), 7.12 (d, 1H, J=1.5 Hz), 6.77 (d, 1H, J=1.5 Hz), 4.58 (heptet, 1H,J=6.3 Hz), 4.04 (m, 1H), 3.70 (s, 3H), 3.64 (s, 2H), 2.32 (s, 3H),2.10-1.95 (m, 2H), 1.84-1.78 (m, 1H), 1.66-1.60 (m, 1H), 1.40-1.26 (m,1H), 1.39 and 1.35 (2d, 6H, J=6.3 Hz), 1.34 (s, 3H), 1.19 (s, 3H),0.29-0.22 (m, 2H), 0.083-0.00 (m, 2H).

{4-[5-(Cyclopropyl-methyl-amino)-4-isopropoxy-8,8-dimethyl-5,6,7,8-tetrahydronaphthalen-2-ylethynyl]-phenyl}-aceticacid Compound 41

A solution of{4-[5-(cyclopropyl-methyl-amino)-4-isopropoxy-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-ylethynyl]-phenyl}-aceticacid methyl ester (Intermediate 129, 0.045 g, 0.098 mmol) in methanol (2mL) and tetrahydrofuran (2 mL) was treated with 2M lithium hydroxide (1mL, 2 mmol) and the resulting reaction mixture was stirred at ambienttemperature for 2 h. The volatiles were evaporated in vacuo to a residuethat was neutralized with saturated aqueous ammonium chloride solutionand extracted with ethyl acetate. The organic phase was washed withwater and brine, and dried over anhydrous magnesium sulfate, filteredand evaporated in vacuo to a residue that was subjected to flash columnchromatography over silica gel (230-400 mesh) using 5% methanol in ethylacetate as the eluent to afford the title product as a white solid(0.027 g, 61%).

¹H NMR (300 MHz, CDCl₃): δ 7.46 (d, 2H, J=8.1 Hz), 7.29 (d, 2H, J=8.1Hz), 7.14 (d, 1H, J=1.2 Hz), 6.80 (d, 1H, J=1.2 Hz), 4.62 (heptet, 1H,J=6.0 Hz), 4.31 (m, 1H), 3.58 (s, 2H), 2.46 (s, 3H), 2.46-2.39 (m, 1H),2.14-1.87 (m, 2H), 1.72-1.67 (m, 1H), 1.42-1.23 (m, 1H), 1.40 and 1.34(2d, 6H, J=6.0 Hz), 1.31 (s, 3H), 1.16 (s, 3H), 0.80-0.70 (m, 1H),0.53-0.38 (m, 2H), 0.23-0.18 (m, 1H).

2-(3-Bromo-phenyl)-2-methyl-propionic acid ethyl ester Intermediate 130

A solution of 2-(3-bromo-phenyl)-2-methyl-propionitrile (prepared asdescribed by Barlaam et al. J. Med. Chem., 1999, 42, 23, 4890-4908incorporated herein by reference; 1.4 g, 6.24 mmol) was dissolved inethanol (40 mL), treated with concentrated sulfuric acid (1 mL) and theresulting reaction mixture was refluxed for 36 h. The reaction mixturewas cooled to ambient temperature, diluted with water and extracted withethyl acetate. The organic phase was washed with water and brine, driedover anhydrous magnesium sulfate, filtered and evaporated in vacuo to aresidue that was subjected to flash column chromatography over silicagel (230-400 mesh) using 5% ethyl acetate in hexane as the eluent toafford the title product as an orange oil (0.77 g, 46%).

¹H NMR (300 MHz, CDCl₃): δ 7.48 (s, 1H), 7.36 (dd, 1H, J=2.8, 7.7 Hz),7.26 (dd, 1H, J=2.8, 8.3 Hz), 7.20 (dd, 1H, J=7.8, 8.3 Hz), 4.12 (q, 2H,J=7.0 Hz), 1.55 (s, 6H), 1.18 (t, 311, J=7.0 Hz).

2-Methyl-2-(3-trimethylsilanylethynyl-phenyl)-propionic acid ethyl esterIntermediate 131

Following General Procedure D and using2-(3-bromo-phenyl)-2-methyl-propionic acid ethyl ester (Intermediate130, 0.77 g, 2.84 mmol), triethyl amine (5 mL), copper(I)iodide (0.044g, 0.23 mmol), trimethylsilyl acetylene (2 mL, 14.1 mmol) anddichlorobis(triphenylphosphine)palladium(II) (0.159 g, 0.23 mmol)followed by flash column chromatography over silica gel (230-400 mesh)using hexane to 5% ethyl acetate in hexane as the eluent, the titlecompound (0.74 g, 90%) was obtained as an orange oil.

¹H NMR (300 MHz, CDCl₃): δ 7.45 (s, 1H), 7.33-7.24 (m, 3H), 4.12 (q, 2H,J=7.0 Hz), 1.56 (s, 6H), 1.17 (t, 3H, J=7.0 Hz), 0.25 (s, 9H).

2-(3-Ethynyl-phenyl)-2-methyl-propionic acid ethyl ester Intermediate132

A solution of 2-methyl-2-(3-trimethylsilanylethynyl-phenyl)-propionicacid ethyl ester (Intermediate 131, 0.74 g, 2.56 mmol) in ethanol (10mL) was treated with potassium carbonate (0.2 g, 1.45 mmol). Theresulting reaction mixture was stirred at ambient temperature overnight.The volatiles were evaporated in vacuo and the residue was diluted withwater and extracted with diethyl ether. The organic phase was washedwith water and brine, dried over anhydrous magnesium sulfate, filteredand evaporated in vacuo to a residue that was subjected to flash columnchromatography over silica gel (230-400 mesh) using 1-5% ethyl acetatein hexane as the eluent to afford the title product (0.4 g, 72%).

¹H NMR (300 MHz, CDCl₃): δ 7.56 (s, 1H), 7.45-7.33 (m, 3H), 4.18 (q, 2H,J=7.0 Hz), 3.14 (s, 1H), 1.63 (s, 6H), 1.24 (t, 3H, J=7.0 Hz).

2-[3-(4-Methoxycarbonylmethyl-phenylethynyl)-phenyl]-2-methyl-propionicacid ethyl ester Intermediate 133

Following General Procedure B and using2-(3-ethynyl-phenyl)-2-methyl-propionic acid ethyl ester (Intermediate132, 0.101 g, 0.47 mmol), 4-iodo phenyl acetic acid methyl ester (0.129g, 0.47 mmol), triethyl amine (8 mL), copper(I)iodide (0.01 g, 0.05mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.035 g, 0.05mmol) followed by flash column chromatography over silica gel (230-400mesh) using 10-15% ethyl acetate in hexane as the eluent, the titlecompound was obtained as an oil (0.14 g, 82%).

¹H NMR (300 MHz, CDCl₃): δ 7.52-7.25 (m, 8H), 4.13 (q, 2H, J=7.0 Hz),3.70 (s, 3H), 3.64 (s, 2H), 1.58 (s, 6H), 1.18 (t, 3H, J=7.0 Hz).

2-[3-(4-Methoxycarbonylmethyl-phenylethynyl)-phenyl]-2-methyl-propionicacid Compound 42

A solution of2-[3-(4-methoxycarbonylmethyl-phenylethynyl)-phenyl]-2-methyl-propionicacid ethyl ester (Intermediate 133, 0.12 g, 0.33 mmol) in ethanol (2 mL)and tetrahydrofuran (2 mL) was treated with 2M lithium hydroxide (1 mL,2 mmol) and the resulting reaction mixture was stirred at ambienttemperature for 1 h. The volatiles were evaporated in vacuo to a residuethat was neutralized with saturated aqueous ammonium chloride solutionand extracted with ethyl acetate. The organic phase was washed withwater and brine, and dried over anhydrous magnesium sulfate, filteredand evaporated in vacuo to afford the title product as an oil (0.11 g,95%).

¹H NMR (300 MHz, CDCl₃): δ 7.48 (s, 1H), 7.35-7.04 (m, 7H), 4.11 (q, 2H,J=7.0 Hz), 3.32 (s, 2H), 1.50 (s, 6H), 1.11 (t, 3H, J=7.0 Hz).

2-[3-(3-Fluoro-4-methoxycarbonylmethyl-phenylethynyl)-phenyl]-2-methyl-propionicacid ethyl ester Intermediate 134

Following General Procedure B and using2-(3-ethynyl-phenyl)-2-methyl-propionic acid ethyl ester (Intermediate132, 0.10 g, 0.46 mmol), 2-fluoro-4-iodo phenyl acetic acid methyl ester(0.136 g, 0.46 mmol), triethyl amine (8 mL), copper(I)iodide (0.01 g,0.05 mmol) and dichlorobis(triphenylphosphine)-palladium(11) (0.035 g,0.05 mmol) followed by flash column chromatography over silica gel(230-400 mesh) using 10-15% ethyl acetate in hexane as the eluent, thetitle compound was obtained as an oil (0.15 g, 85%).

¹H NMR (300 MHz, CDCl₃): δ 7.52 (s, 1H) 7.39-7.21 (m, 6H), 4.13 (q, 2H,J=7.0 Hz), 3.71 (s, 3H), 3.68 (s, 2H), 1.58 (s, 6H), 1.18 (t, 3H, J=7.0Hz).

2-[3-(3-Fluoro-4-methoxycarbonylmethyl-phenylethynyl)-phenyl]-2-methyl-propionicacid Compound 43

A solution of2-[3-(3-fluoro-4-methoxycarbonylmethyl-phenylethynyl)-phenyl]-2-methyl-propionicacid ethyl ester (Intermediate 134, 0.13 g, 0.34 mmol) in ethanol (2 mL)and tetrahydrofuran (2 mL) was treated with 2M lithium hydroxide (1 mL,2 mmol) and the resulting reaction mixture was stirred at ambienttemperature for 45 minutes. The volatiles were evaporated in vacuo to aresidue that was neutralized with saturated aqueous ammonium chloridesolution and extracted with ethyl acetate. The organic phase was washedwith water and brine, and dried over anhydrous magnesium sulfate,filtered and evaporated in vacuo to afford the title product (0.125 g,˜100%).

¹H NMR (300 MHz, CDCl₃): δ 7.48 (s, 1H) 7.34-7.06 (m, 6H), 4.10 (q, 2H,J=7.0 Hz), 3.41 (s, 2H), 1.52 (s, 6H), 1.13 (t, 3H, J=7.0 Hz).

3-Bromo-benzoic acid isopropyl ester Intermediate 135

A solution of 3-bromo benzoic acid (Aldrich, 2.4 g, 11.9 mmol) inisopropanol (20 mL) was treated with 1 mL of concentrated sulfuric acidand the resulting reaction mixture was refluxed overnight. The reactionmixture was then cooled to ambient temperature and diluted with waterand extracted with diethyl ether. The organic phase was dried overanhydrous sodium sulfate, filtered and evaporated to an oil that wassubjected to flash column chromatography over silica gel (230-400 mesh)using 10% ethyl acetate in hexane as the eluent to afford the titlecompound as an oil (2.54 g, 88%).

¹H NMR (300 MHz, CDCl₃): δ 8.14 (s, 1H), 7.95 (d, J=7.6 Hz, 1H), 7.64(d, J=7.6 Hz, 1H), 7.29 (t, J=7.6 Hz, 1H), 5.24 (hept, J=6.1 Hz, 1H),1.35 (d, J=6.1 Hz, 6H).

3-Trimethylsilanylethynyl-benzoic acid isopropyl ester Intermediate 136

Following General Procedure D and using 3-bromo-benzoic acid isopropylester

(Intermediate 135, 1.25 g, 5.14 mmol), triethyl amine (12 mL),copper(I)iodide (0.078 g, 0.41 mmol), trimethylsilyl acetylene (4 mL,28.16 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.288 g,0.41 mmol) followed by flash column chromatography over silica gel(230-400 mesh) using 3% ethyl acetate in hexane as the eluent, the titlecompound (1.25 g, 94%) was obtained as an orange oil.

¹H NMR (300 MHz, CDCl₃): δ 8.09 (s, 1H), 7.96 (d, J=7.6 Hz, 1H), 7.59(d, J=7.6 Hz, 1H), 7.35 (t, J=7.6 Hz, 1H), 5.24 (hept, J=6.1 Hz, 1H),1.35 (d, J=6.1 Hz, 6H), 0.25 (s, 9H).

3-Ethynyl-benzoic acid isopropyl ester Intermediate 137

A solution of 3-trimethylsilanylethynyl-benzoic acid isopropyl ester

(Intermediate 136, 0.6 g, 2.3 mmol) in anhydrous tetrahydrofuran (3 mL)was treated with a 1M solution of tetra-n-butyl ammonium fluoride intetrahydrofuran (4.6 mL, 4.6 mmol) and the resulting reaction mixturewas stirred in an ice bath for 5 min. Water was added and the reactionmixture was extracted with ethyl acetate. The organic phase was washedwith water and brine, dried over anhydrous sodium sulfate, filtered andevaporated to an oil that was purified by flash column chromatographyusing 5%-30% ethyl acetate in hexane as the eluent to afford the titlecompound as a solid (0.33 g, 76%).

¹H NMR (300 MHz, CDCl₃): δ 8.15 (s, 1H), 8.01 (d, J=7.6 Hz, 1H), 7.64(d, J=7.6 Hz, 1H), 7.39 (t, J=7.6 Hz, 1H), 5.25 (hept, J=6.1 Hz, 1H),3.13 (s, 1H), 1.37 (d, J=6.1 Hz, 6H).

3-(4-Ethoxycarbonylmethyl-3-fluoro-phenylethynyl)-benzoic acid isopropylester Intermediate 138

Following General Procedure B and using 3-ethynyl-benzoic acid isopropylester (Intermediate 137, 0.099 g, 0.53 mmol), 2-fluoro-4-iodo phenylacetic acid ethyl ester (0.164 g, 0.53 mmol), triethyl amine (3 mL),copper(I)iodide (0.01 g, 0.05 mmol) anddichlorobis(triphenylphosphine)palladium(II) (0.035 g, 0.5 mmol)followed by flash column chromatography over silica gel (230-400 mesh)using 7-10% ethyl acetate in hexane as the eluent, the title compoundwas obtained as a light orange oil (0.08 g, 92%).

¹H NMR (300 MHz, CDCl₃): δ 8.17 (s, 1H), 8.01 (d, J=7.6 Hz, 1H), 7.67(d, J=7.6 Hz, 1H), 7.42 (t, J=7.6 Hz, 1H), 7.29-7.22 (m, 3H), 5.21(hept, J=6.1 Hz, 1H), 4.18 (q, J=7.1 Hz, 2H), 3.68 (s, 2H), 1.38 (d,J=6.1 Hz, 6H), 1.26 (t, J=7.1 Hz, 3H).

3-(4-Carboxymethyl-3-fluoro-phenylethynyl)-benzoic acid isopropyl esterCompound 44

A solution of 3-(4-ethoxycarbonylmethyl-3-fluoro-phenylethynyl)-benzoicacid isopropyl ester (Intermediate 138, 0.1 g, 0.27 mmol) in isopropanol(2 mL) and tetrahydrofuran (2 mL) was treated with a 2M solution oflithium hydroxide (1 mL, 2 mmol). After 40 min. at ambient temperature,the reaction mixture was concentrated in vacuo a bit, neutralized with10% hydrochloric acid and the solid formed was filtered, washed withwater and dried to afford the title compound (0.09 g, 97%).

¹H NMR (300 MHz, CDCl₃): δ 8.18 (s, 1H), 8.02 (d, J=7.6 Hz, 1H), 7.68(d, J=7.6 Hz, 1H), 7.44 (t, J=7.6 Hz, 1H), 7.31-7.24 (m, 3H), 5.27(hept, J=6.1 Hz, 1H), 3.74 (s, 2H), 1.39 (d, J=6.1 Hz, 6H).

4-Bromo-2-tert-butyl-5-methyl-phenol Intermediate 139

A solution of 4-bromo-3-methylphenol (Aldrich, 5.1 g, 27.3 mmol) inanhydrous dichloromethane (50 mL) was treated with 2-methyl-2-propanol(15 mL) and concentrated sulfuric acid (3 mL) and stirred at ambienttemperature for 3 months. The volatiles were evaporated in vacuo, theresidue was diluted with water and extracted with diethyl ether. Thecombined organic phase was dried over anhydrous magnesium sulfate,filtered and evaporated in vacuo to an oil. Flash column chromatographyusing 3-5% ethyl acetate in hexane as the eluent afforded the titlecompound as a deep yellow oil (3.42 g, 51%). It was used as such for thenext step.

¹H NMR (300 MHz, CDCl₃): δ 7.40 (s, 1H), 6.56 (s, 1H), 5.23 (s, 1H),2.30 (s, 3H), 1.41 (s, 91-1).

3-Bromo-5-tert-butyl-6-hydroxy-2-methyl-benzaldehyde Intermediate 140

A stirred, cooled (ice bath) solution of4-bromo-2-tert-butyl-5-methyl-phenol (Intermediate 139, 0.85 g, 3.5mmol) in anhydrous dichloromethane (7 mL) was treated with titaniumtetrachloride (0.64 mL, 5.8 mmol) followed by α,α-dichloro methyl ether(0.3 g, 3.5 mmol). The reaction mixture was allowed to warm to ambienttemperature for 4 h. The reaction mixture was diluted with diethylether, washed with brine (×1) and dried over anhydrous sodium sulfate,filtered and evaporated in vacuo to a residue which was subjected toflash column chromatography over silica gel (230-400 mesh) using 1%ethyl acetate in hexane to afford the title compound as a yellow solid(0.58 g, 61%).

¹H NMR (300 MHz, CDCl₃): δ 12.89 (s, 1H), 10.32 (s, 1H), 7.60 (s, 1H),2.63 (s, 3H), 1.38 (s, 9H).

3-Bromo-5-tert-butyl-6-isopropoxy-2-methyl-benzaldehyde Intermediate 141

A stirred, cooled (ice bath) solution of3-bromo-5-tert-butyl-6-hydroxy-2-methyl-benzaldehyde (Intermediate 140,0.58 g, 2.14 mmol) in anhydrous N,N-dimethylformamide (10 mL) wastreated with sodium hydride (0.34 g of 60% suspension in mineral oil,8.56 mmol). After 30 minutes, 2-iodopropane (1.3 mL, 12.84 mmol) wasadded and the reaction mixture was heated at 75° C. overnight. Thereaction mixture was then cooled and poured into iced water andextracted with diethyl ether. The organic extract was then washed withwater and brine, dried over anhydrous magnesium sulfate, filtered andevaporated in vacuo to an oil. Flash column chromatography using 2-4%ethyl acetate in hexane as the eluent afforded the title product (0.43g, 64%).

¹H NMR (300 MHz, CDCl₃): δ 10.23 (s, 1H), 7.68 (s, 1H), 4.34 (heptet,1H, J=6.2 Hz), 2.57 (s, 3H), 1.40 (s, 9H), 1.28 (d, 6H, J=6.2 Hz).

3-tert-Butyl-2-isopropoxy-6-methyl-5-trimethylsilanylethynyl-benzaldehydeIntermediate 142

Following General Procedure D and using3-bromo-5-tert-butyl-6-isopropoxy-2-methyl-benzaldehyde (Intermediate141, 0.43 g, 1.37 mmol), triethyl amine, copper(I)iodide (0.021 g, 0.11mmol), trimethylsilyl acetylene (1 mL), anddichlorobis(triphenylphosphine)palladium(II) (0.077 g, 0.11 mmol)followed by flash column chromatography over silica gel (230-400 mesh)using 2% ethyl acetate in hexane as the eluent, the title compound wasobtained (0.45 g, ˜100%).

¹H NMR (300 MHz, CDCl₃): δ 10.10 (s, 1H), 7.41 (s, 1H), 4.19 (heptet,1H, J=6.1 Hz), 2.44 (s, 3H), 1.21 (s, 9H), 1.09 (d, 6H, J=6.1 Hz), 0.08(s, 9H).

3-tert-Butyl-5-ethynyl-2-isopropoxy-6-methyl-benzaldehyde Intermediate143

A solution of3-tert-butyl-2-isopropoxy-6-methyl-5-trimethylsilanylethynyl-benzaldehyde(Intermediate 142, 0.45 g, 1.37 mmol) in methanol (5 mL) andtetrahydrofuran was treated with potassium carbonate (0.2 g, 1.45 mmol)and the resulting reaction mixture was stirred at ambient temperaturefor 3 h. The reaction mixture was evaporated in vacuo and the residuewas extracted with diethyl ether and washed with water and brine. Theorganic phase was dried, filtered and evaporated in vacuo to afford thetitle compound (0.35 g, 90%).

¹H NMR (300 MHz, CDCl₃): δ 10.28 (s, 1H), 7.63 (s, 1H), 4.38 (heptet,1H, J=6.2 Hz), 3.48 (s, 1H), 2.63 (s, 3H), 1.39 (s, 9H), 1.29 (d, 6H,J=6.2 Hz).

[4-(5-tert-Butyl-3-formyl-4-isopropoxy-2-methyl-phenylethynyl)-phenyl]-aceticacid methyl ester Intermediate 144

Following General Procedure B and using3-tert-butyl-5-ethynyl-2-isopropoxy-6-methyl-benzaldehyde (Intermediate143, 0.35 g, 1.35 mmol), 4-iodo phenyl acetic acid methyl ester (0.374g, 1.35 mmol), triethyl amine (8 mL), copper(I)iodide (0.02 g, 0.1 mmol)and dichlorobis(triphenylphosphine)palladium(II) (0.072 g, 0.1 mmol)followed by flash column chromatography over silica gel (230-400 mesh)using 3-5% ethyl acetate in hexane as the eluent, the title compound wasobtained as a white solid (0.37 g, 75%).

¹H NMR (300 MHz, CDCl₃): δ 10.29 (s, 1H), 7.65 (s, 1H), 7.48 (d, 2H,J=8.2 Hz), 7.53 (d, 2H, J=8.2 Hz), 4.38 (heptet, 1H, J=6.1 Hz), 3.68 (s,3H), 3.62 (s, 2H), 2.68 (s, 3H), 1.41 (s, 9H), 1.27 (d, 6H, J=6.1 Hz).

[4-(5-tert-Butyl-3-ethynyl-4-isopropoxy-2-methyl-phenylethynyl)-phenyl]-aceticacid methyl ester Intermediate 145

Anhydrous tetrahydrofuran (3 mL) was added to a 2M solution oftrimethylsilyl diazomethane in hexanes (0.37 mL, 0.74 mmol) and theresulting reaction mixture was cooled to −78° C. A solution of 1.6Mn-butyl lithium in hexanes (0.5 mL, 0.8 mmol) was added followed, after30 minutes, by a solution of[4-(5-tert-butyl-3-formyl-4-isopropoxy-2-methyl-phenylethynyl)-phenyl]-aceticacid methyl ester (Intermediate 144, 0.2 g, 0.49 mmol) in anhydroustetrahydrofuran and the resulting reaction mixture was stirred at −78°C. for 1 h and at 0° C. for 40 minutes. The reaction mixture was thenquenched with saturated aqueous ammonium chloride solution and extractedwith diethyl ether. The organic phase was washed with brine, dried overanhydrous magnesium sulfate, filtered and evaporated in vacuo to aresidue that was subjected to flash column chromatography over silicagel (230-400 mesh) using 2.5-4% ethyl acetate in hexane as the eluentfollowed by preparative normal phase HPLC using 5% ethyl acetate inhexane as the mobile phase to afford the title product as a colorlessoil (0.023 g, 11.6%). ¹H NMR (300 MHz, CDCl₃): δ 7.49 (d, 2H, J=8.0 Hz),7.44 (s, 1H), 7.26 (d, 2H, J=8.0 Hz), 5.76 (heptet, 1H, J=6.1 Hz), 3.70(s, 3H), 3.64 (s, 2H), 3.58 (s, 1H), 2.58 (s, 3H), 1.39 (s, 9H), 1.31(d, 6H, J=6.1 Hz).

[4-(5-tert-Butyl-3-ethynyl-4-isopropoxy-2-methyl-phenylethynyl)-phenyl]-aceticacid Compound 45

A solution of[4-(5-tert-butyl-3-ethynyl-4-isopropoxy-2-methyl-phenylethynyl)-phenyl]-aceticacid methyl ester (Intermediate 145, 0.023 g, 0.057 mmol) in methanol(1.5 mL) and tetrahydrofuran (1.5 mL) was treated with 1M lithiumhydroxide (0.5 mL, 1 mmol) and the resulting reaction mixture wasstirred at ambient temperature for 45 minutes. The volatiles wereevaporated in vacuo to a residue that was neutralized with saturatedaqueous ammonium chloride solution and extracted with ethyl acetate. Theorganic phase was washed with water and brine, and dried over anhydrousmagnesium sulfate, filtered and evaporated in vacuo to afford the titleproduct (0.020 g, 91%).

¹H NMR (300 MHz, CDCl₃): δ 7.47 (d, 2H, J=8.0 Hz), 7.43 (s, 1H), 7.24(d, 2H, J=8.0 Hz), 5.75 (heptet, 1H, J=6.1 Hz), 3.62 (s, 2H), 3.57 (s,1H), 2.57 (s, 3H), 1.38 (s, 9H), 1.30 (d, 6H, J=6.1 Hz).

[4-(5-tert-Butyl-4-isopropoxy-2-methyl-3-vinyl-phenylethynyl)-phenyl]-aceticacid methyl ester Intermediate 146

A solution of methylidene triphenyl phosphorane [5 mL of 0.1M solution,0.5 mmol, generated from methyl triphenylphosphonium bromide (2.5 g, 7mmol) and 1.6M n-butyllithium solution in hexanes (2.9 mL, 4.7 mmol) in50 mL of tetrahydrofuran] was added to a solution of[4-(5-tert-butyl-3-formyl-4-isopropoxy-2-methyl-phenylethynyl)-phenyl]-aceticacid methyl ester (Intermediate 144, 0.052 g, 0.13 mmol) intetrahydrofuran (1 mL). After 1 h the reaction mixture was quenched withwater and extracted with ethyl acetate. The organic phase was washedwith water and brine, dried over anhydrous sodium sulfate, filtered andevaporated in vacuo to a clear oil that after flash columnchromatography over silica gel (230-400 mesh) using 5% ethyl acetate inhexane as the eluent afforded the title compound (0.02 g, 39%).

¹H NMR (300 MHz, CDCl₃): δ 7.48 (d, 2H, J=7.9 Hz), 7.39 (s, 1H), 7.25(d, 2H, J=7.9 Hz), 6.73 (dd, 1H, J=11.4, 17.9 Hz), 5.49 (dd, 1H, J=2.0,11.4 Hz), 5.37 (dd, 1H, J=2.1, 17.9 Hz), 4.93 (heptet, 1H, J=6.4 Hz),3.70 (s, 3H), 3.63 (s, 2H), 2.44 (s, 3H), 1.40 (s, 9H), 1.17 (d, 6H,J=6.4 Hz).

[4-(5-tert-Butyl-4-isopropoxy-2-methyl-3-vinyl-phenylethynyl)-phenyl]-aceticacid Compound 46

A solution of[4-(5-tert-butyl-4-isopropoxy-2-methyl-3-vinyl-phenylethynyl)-phenyl]-aceticacid methyl ester (Intermediate 146, 0.02 g, 0.049 mmol) in methanol(1.5 mL) and tetrahydrofuran (1.5 mL) was treated with 1M lithiumhydroxide (0.5 mL, 1 mmol) and the resulting reaction mixture wasstirred at ambient temperature for 45 minutes. The volatiles wereevaporated in vacuo to a residue that was neutralized with saturatedaqueous ammonium chloride solution and extracted with ethyl acetate. Theorganic phase was washed with water and brine, and dried over anhydrousmagnesium sulfate, filtered and evaporated in vacuo to afford the titleproduct (0.020 g, ˜100%).

¹H NMR (300 MHz, CDCl₃): δ 7.48 (d, 2H, J=8.2 Hz), 7.39 (s, 1H), 7.24(d, 2H, J=8.2 Hz), 6.72 (dd, 1H, J=11.4, 17.9 Hz), 5.49 (dd, 1H, J=2.0,11.4 Hz), 5.37 (dd, 1H, J=2.1, 17.9 Hz), 4.92 (heptet, 1H, J=6.2 Hz),3.64 (s, 2H), 2.43 (s, 3H), 1.40 (s, 9H), 1.17 (d, 6H, J=6.2 Hz).

[4-(5-tert-Butyl-3-hydroxymethyl-4-isopropoxy-2-methyl-phenylethynyl)-phenyl]-aceticacid methyl ester Intermediate 147

A stirred, cooled (ice bath) solution of[4-(5-tert-butyl-3-formyl-4-isopropoxy-2-methyl-phenylethynyl)-phenyl]-aceticacid methyl ester (Intermediate 142, 0.172 g, 0.42 mmol) in methanol (4mL) was treated with sodium borohydride (0.02 g, 0.51 mmol) and theresulting reaction mixture was stirred for 1.5 h. The reaction mixturewas quenched with water and extracted with diethyl ether. The organicphase was washed with water (×1) and brine (×1), dried over anhydroussodium sulfate, filtered and evaporated in vacuo to a residue that wassubjected to flash column chromatography over silica gel (230-400 mesh)using 15-20% ethyl acetate in hexane as the eluent to afford the titleproduct as a white solid (0.15 g, 88%).

¹H NMR (300 MHz, CDCl₃): δ 7.48 (d, 2H, J=8.5 Hz), 7.47 (s, 1H), 7.25(d, 2H, J=8.5 Hz), 4.74 (br s, 2H), 4.74-4.60 (m, 1H), 3.69 (s, 3H),3.63 (s, 2H), 2.60 (s, 3H), 1.40 (s, 9H), 1.27 (d, 6H, J=6.2 Hz).

[4-(3-Bromomethyl-5-tert-butyl-4-isopropoxy-2-methyl-phenylethynyl)-phenyl]-aceticacid methyl ester Intermediate 148

A stirred, cooled (ice bath) solution of[4-(5-tert-butyl-3-hydroxymethyl-4-isopropoxy-2-methyl-phenylethynyl)-phenyl]-aceticacid methyl ester (Intermediate 147, 0.15 g, 0.37 mmol) andtriphenylphosphine (0.125 g, 0.48 mmol) in anhydrous dichloromethane (5mL) was treated with N-bromo succinimide (0.085 g, 0.48 mmol) underargon and the resulting reaction mixture was allowed to warm to ambienttemperature and stirred overnight. The reaction mixture was quenchedwith dilute, aqueous sodium bicarbonate solution and extracted withdiethyl ether. The organic phase was washed with water (×1) and brine(×1), dried over anhydrous magnesium sulfate, filtered and evaporated invacuo to a residue that on flash column chromatography over silica gel(230-400 mesh) using 4-5% ethyl acetate in hexane as the eluent affordedthe title compound (0.12 g, 69%) as a colorless oil. It was used as suchfor the next step.

{4-[5-tert-Butyl-4-isopropoxy-2-methyl-3-(3-trimethylsilanyl-prop-2-ynyl)-phenylethynyl]-phenyl}-aceticacid methyl ester Intermediate 149

A solution of[4-(3-bromomethyl-5-tert-butyl-4-isopropoxy-2-methyl-phenylethynyl)-phenyl]-aceticacid methyl ester (Intermediate 148, 0.12 g, 0.25 mmol) in triethylamine (1 mL) and N,N-dimethylformamide (4 mL) was sparged with argon andtreated with trimethylsilylacetylene (0.5 mL, 3.5 mmol) anddichlorobis(triphenylphosphine)palladium(II) (0.025 g, 0.036 mmol). Theresulting reaction mixture was heated at 85° C. overnight at the end ofwhich it was cooled to ambient temperature and subjected to flash columnchromatography over silica gel (230-400 mesh) using 4% ethyl acetate inhexane as the eluent followed by preparative normal phase HPLC using 3%ethyl acetate in hexane as the mobile phase to afford the title compoundas an oil (0.038 g, 31%).

1H NMR (300 MHz, CDCl₃): δ 7.50 (d, 2H, J=7.9 Hz), 7.48 (s, 1H), 7.26(d, 2H, J=7.9 Hz), 4.89 (heptet, 1H, J=6.5 Hz), 3.70 (s, 3H), 3.64 (s,2H), 3.50 (s, 2H), 2.57 (s, 3H), 1.40 (s, 9H), 1.27 (d, 6H, J=6.5 Hz),0.12 (s, 9H).

[4-(5-tert-Butyl-4-isopropoxy-2-methyl-3-prop-2-ynyl-phenylethynyl)-phenyl]-aceticacid Compound 47

A solution of{4-[5-tert-butyl-4-isopropoxy-2-methyl-3-(3-trimethylsilanyl-prop-2-ynyl)-phenylethynyl]-phenyl}-aceticacid methyl ester (Intermediate 149, 0.038 g, 0.078 mmol) in methanol(1.5 mL) and tetrahydrofuran (1.5 mL) was treated with 2M lithiumhydroxide (1 mL, 2 mmol) and the resulting reaction mixture was stirredat ambient temperature for 1.5 h. The volatiles were evaporated in vacuoto a residue that was neutralized with saturated aqueous ammoniumchloride solution and extracted with ethyl acetate. The organic phasewas washed with water and brine, and dried over anhydrous magnesiumsulfate, filtered and evaporated in vacuo to afford the title product(0.032 g, 98%). ¹H NMR (300 MHz, CDCl₃): δ 7.50 (d, 2H, J=8.1 Hz), 7.43(s, 1H), 7.27 (d, 2H, J=8.1 Hz), 4.82 (heptet, 1H, J=6.4 Hz), 3.67 (s,2H), 3.48 (d, 2H, J=2.5 Hz), 2.58 (s, 3H), 1.39 (s, 9H), 1.28 (d, 6H,J=6.4 Hz).

4-(2-Bromo-4-methoxy-phenyl)-4-oxo-butyric acid ethyl ester Intermediate150

A stirred, cooled (−30° C.) solution of 3-bromo anisole (18.7 g, 100mmol) and ethyl succinyl chloride (21 mL, 150 mmol) in anhydrousdichloromethane (200 mL) was treated with aluminum chloride (26.6 g, 200mmol) and the reaction mixture was allowed to warm to ambienttemperature and stirred overnight. The reaction mixture was poured intowater and extracted with dichloromethane (×2). The combined organicphase was washed with brine, dried over anhydrous sodium sulfate,filtered and evaporated in vacuo to a brown oil. A solid separated outon standing. The supernatant liquid was decanted and the solid waswashed with 1:3 dichloromethane:hexane and dried to afford the isomer4-(4-bromo-2-methoxy-phenyl)-4-oxo-butyric acid ethyl ester. Thecombined mother liquor and washings was evaporated to a brown oil thatwas subjected to flash column chromatography over silica gel (230-400mesh) using 15% ethyl acetate in hexane as the eluent to afford theisomer 4-(4-bromo-2-methoxy-phenyl)-4-oxo-butyric acid ethyl ester(overall 12 g, 38%), and the title compound (11.4 g, 36%) and a 1:1mixture of both (2 g, 6.3%).

¹H NMR (300 MHz, CDCl₃): δ 7.59 (d, 1H, J=8.8 Hz), 7.14 (d, 1H, J=2.6Hz), 6.87 (dd, 1H, J=2.6, 8.8 Hz), 4.14 (q, 2H, J=7.0 Hz), 3.83 (s, 3H),3.23 (t, 2H, J=6.4 Hz), 2.74 (t, 2H, J=6.4 Hz), 1.25 (t, 3H, J=7.0 Hz).

4-(2-Bromo-4-methoxy-phenyl)-butyric acid ethyl ester Intermediate 151

A solution of 4-(2-bromo-4-methoxy-phenyl)-4-oxo-butyric acid ethylester (Intermediate 150, 6.45 g, 20.5 mmol) in trifluoroacetic acid (32mL, 409 mmol) was treated with triethylsilane (14.4 mL, 90 mmol) and theresulting reaction mixture was heated at 55° C. for 3 h. The reactionmixture was then cooled to ambient temperature, neutralized with solidsodium bicarbonate, diluted with water and extracted with diethyl ether.The organic phase was washed with water and brine, dried over anhydrousmagnesium sulfate, filtered and evaporated in vacuo to afford the titlecompound (5.4 g, 88%) as a colorless oil.

¹H NMR (300 MHz, CDCl₃): δ 7.11 (d, 1H, J=8.2 Hz), 7.08 (d, 1H, J=2.6Hz), 6.79 (dd, 1H, J=2.6, 8.2 Hz), 4.13 (q, 2H, J=7.3 Hz), 3.76 (s, 3H),2.71 (t, 2H, J=7.6 Hz), 2.34 (t, 2H, J=7.6 Hz), 1.92 (quintet, 2H, J=7.6Hz), 1.26 (t, 3H, J=7.3 Hz).

5-(2-Bromo-4-methoxy-phenyl)-2-methyl-pentan-2-ol Intermediate 152

A stirred, cooled (−10° C.) solution of4-(2-bromo-4-methoxy-phenyl)-butyric acid ethyl ester (Intermediate 151,5.4 g, 18 mmol) in anhydrous tetrahydrofuran (100 mL) was treated with a3M solution of methyl magnesium bromide (16 mL, 48 mmol) and theresulting reaction mixture was allowed to warm to ambient temperatureover 3 h. It was quenched with saturated, aqueous ammonium chloridesolution, diluted with water and extracted with diethyl ether. Theorganic phase was washed with water and brine, dried over anhydrousmagnesium sulfate, filtered and evaporated in vacuo to afford the titleproduct as a viscous oil (5.16 g, ˜100%).

¹H NMR (300 MHz, CDCl₃): δ 7.11 (d, 11, J=8.5 Hz), 7.08 (d, 1H, J=2.6Hz), 6.78 (dd, 1H, J=2.6, 8.5 Hz), 3.77 (s, 3H), 2.67 (t, 2H, J=7.3 Hz),1.69-1.43 (m, 4H), 1.21 (s, 6H).

5-Bromo-2-methoxy-1,1-dimethyl-1,2,3,4-tetrahydro-naphthaleneIntermediate 153

5-(2-Bromo-4-methoxy-phenyl)-2-methyl-pentan-2-ol (Intermediate 152,5.16 g, 17.9 mmol) was treated with 85% sulfuric acid (50 mL) at ambienttemperature. After 30 minutes, the reaction mixture was diluted withcold water and extracted with diethyl ether. The organic phase waswashed with water and brine, dried over anhydrous magnesium sulfate,filtered and evaporated in vacuo to afford the title product (4.63 g,96%) as a pale yellow oil.

¹H NMR (300 MHz, CDCl₃): δ 6.96 (d, 1H, J=2.6 Hz), 6.86 (d, 1H, J=2.6Hz), 3.76 (s, 3H), 2.68 (t, 2H, J=6.7 Hz), 1.83-1.75 (m, 2H), 1.62-1.58(m, 2H), 1.26 (s, 6H).

8-Bromo-6-methoxy-4,4-dimethyl-3,4-dihydro-2H-naphthalen-1-oneIntermediate 154

A solution of5-bromo-2-methoxy-1,1-dimethyl-1,2,3,4-tetrahydro-naphthalene(Intermediate 153, 4.6 g, 17.1 mmol) in glacial acetic acid (20 mL) wascooled to 0° C. and treated with a solution of chromium trioxide (5.5 g,55 mmol) in acetic acid and water (20 mL each). The reaction mixture wasthen allowed to warm to ambient temperature and stirred for 24 h. It wasdiluted with water and extracted with diethyl ether (×2). The combinedorganic phase was washed with water (×3), saturated aqueous sodiumbicarbonate (×1) and brine (×1), dried over anhydrous magnesium sulfate,filtered and evaporated in vacuo to afford the title compound (3.9 g,81%) as a yellow oil.

¹H NMR (300 MHz, CDCl₃): δ 7.09 (d, 1H, J=2.6 Hz), 6.87 (d, 1H, J=2.61Hz), 3.85 (s, 3H), 2.71 (t, 2H, J=7.0 Hz), 1.96 (t, 2H, J=7.0 Hz), 1.35(s, 6H).

6-Methoxy-4,4-dimethyl-8-vinyl-3,4-dihydro-2H-naphthalen-1-oneIntermediate 155

A solution of8-bromo-6-methoxy-4,4-dimethyl-3,4-dihydro-2H-naphthalen-1-one(Intermediate 154, 2.83 g, 10 mmol) and tributyl(vinyl)tin (3 mL, 10mmol) in anhydrous N,N-dimethyl formamide (30 mL) was sparged with argonand treated with tetrakis(triphenylphosphine)palladium (0) (0.3 g, 0.26mmol). The resulting reaction mixture was heated to 91° C. for two daysat the end of which it was cooled to ambient temperature, diluted withwater and extracted with diethyl ether (×2). The combined organic phasewas washed with water (×1), and brine (×1), dried over anhydrousmagnesium sulfate, filtered and evaporated to a pale yellow oil. Flashchromatography using 15% ethyl acetate in hexane as the eluent affordedthe title product (1.7 g, 73%) as a pale yellow oil.

¹H NMR (300 MHz, CDCl₃): δ 7.50 (dd, 1H, J=10.8, 17.3 Hz), 6.85 (s, 2H),5.50 (dd, 1H, J=1.4, 17.3 Hz), 5.28 (dd, 1H, J=1.4, 10.8 Hz), 3.88 (s,3H), 2.68 (t, 2H, J=6.7 Hz), 1.95 (t, 2H, J=6.7 Hz), 1.35 (s, 6H).

8-Cyclopropyl-6-methoxy-4,4-dimethyl-3,4-dihydro-2H-naphthalen-1-oneIntermediate 156

A stirred, cooled (−40° C.) solution of6-methoxy-4,4-dimethyl-8-vinyl-3,4-dihydro-2H-naphthalen-1-one(Intermediate 155, 51.7 g, 7.4 mmol) in diethyl ether (10 mL) wastreated with a solution of diazomethane in ether (40 mmol in 50 mL ofether) followed by palladium(II) acetate (0.08 g) and the resultingreaction mixture was warmed to −25° C. when effervescence was observed.The reaction mixture was then filtered through a plug of silica and thefiltrate was evaporated to afford a dark brown residue that wassubjected to flash column chromatography over silica gel (23-400 mesh)using 20% ethyl acetate in hexane as the eluent to afford the titleproduct as a pale yellow solid (1.5 g, 83%).

¹H NMR (300 MHz, CDCl₃): δ 6.71 (d, 1H, J=2.6 Hz), 6.44 (d, 1H, J=2.6Hz), 3.82 (s, 3H), 2.98 (m, 1H), 2.69 (t, 2H, J=6.7 Hz), 1.94 (t, 2H,J=6.7 Hz), 1.34 (s, 6H), 1.02-0.88 (m, 2H), 0.65-0.59 (m, 2H).

8-Cyclopropyl-6-hydroxy-3,4-dihydro-2H-naphthalen-1-one Intermediate 157

A solution of8-cyclopropyl-6-methoxy-4,4-dimethyl-3,4-dihydro-2H-naphthalen-1-one(Intermediate 156, 1.5 g, 6.14 mmol) and sodium cyanide (2 g, 40.8 mmol)in anhydrous dimethylsulfoxide (25 mL) was heated at 230° C. overnightunder argon. The reaction mixture was then cooled to ambienttemperature, poured into ice and acidified (Caution! Hydrogen cyanideevolution!) with dilute hydrochloric acid and extracted with ethylacetate (×2). The combined organic extract was washed with brine (×1),dried over anhydrous sodium sulfate, filtered and evaporated to afford adark brown oil. Flash column chromatography on silica gel (230-400 mesh)using 25% ethyl acetate in hexane as the eluent afforded the titlecompound as a solid (1.1 g, 78%).

¹H NMR (300 MHz, CD₃COCD₃): δ 8.14 (s, 1H), 6.75 (d, 1H, J=2.4 Hz), 6.40(d, 1H, J=2.4 Hz), 3.02 (m, 1H), 2.62 (t, 2H, J=6.8 Hz), 1.94 (t, 2H,J=6.8 Hz), 1.33 (s, 6H), 0.93-0.89 (m, 2H), 0.59-0.55 (m, 2H).

Trifluoro-methanesulfonic acid4-cyclopropyl-8,8-dimethyl-5-oxo-5,6,7,8-tetrahydro-naphthalen-2yl esterIntermediate 158

A solution of8-cyclopropyl-6-hydroxy-4,4-dimethyl-3,4-dihydro-2H-naphthalen-1-one(Intermediate 157, 1.1 g, 4.78 mmol) and 4-dimethylaminopyridine (1.22g, 10 mmol) in anhydrous dichloromethane (20 mL) was treated2-[N,N-bis(trifluoromethylsulfonyl)amino]-5-chloro-pyridine (2.07 g,5.26 mmol) under argon at ambient temperature. After 3.5 h, the reactionmixture was subjected to flash column chromatography on silica gel(230-400 mesh) using 10% ethyl acetate in hexane as the eluent to affordthe title compound as solid (1.76 g, 100%).

¹H NMR (300 MHz, CDCl₃): δ 7.10 (d, 1H, J=2.3 Hz), 6.78 (d, 1H, J=2.3Hz), 2.90 (m, 1H), 2.78 (t, 2H, J=7.0 Hz), 2.01 (t, 2H, J=7.0 Hz), 1.38(s, 6H), 1.10-1.04 (m, 2H), 0.67-0.62 (m, 2H).

8-Cyclopropyl-4,4-dimethyl-6-(trimethylsilanyl)ethynyl-3,4-dihydro-2H-naphthalen-1-oneIntermediate 159

Following General Procedure B and using trifluoro-methanesulfonic acid4-cyclopropyl-8,8-dimethyl-5-oxo-5,6,7,8-tetrahydro-naphthalen-2yl ester(Intermediate 158, 1.09 g, 3 mmol), triethyl amine (5 mL),tetrahydrofuran (5 mL), copper(I)iodide (0.12 g, 0.6 mmol),dichlorobis(triphenylphosphine)palladium(II) (0.42 g, 0.6 mmol) and(trimethylsilyl)acetylene (2.2 mL, 15 mmol) followed by flash columnchromatography over silica gel (230-400 mesh) using 7% ethyl acetate inhexane as the eluent, the title compound was obtained as an orange oil(1.05 g, quantitative).

¹H NMR (300 MHz, CDCl₃): δ 7.29 (d, 1H, J=1.2 Hz), 6.98 (d, 1H, J=1.2Hz), 2.81 (m, 1H), 2.72 (t, 2H, J=6.7 Hz), 1.95 (t, 2H, J=6.7 Hz), 10.34(s, 6H), 1.01-0.95 (m, 2H), 0.66-0.61 (m, 2H), 0.26 (s, 9H).

8-Cyclopropyl-4,4-dimethyl-6-ethynyl-1-tetralone Intermediate 160

Following General Procedure F and using8-cyclopropyl-4,4-dimethyl-6-(trimethylsilanyl)ethynyl-1-tetralone(Intermediate 159, 1.05 g, 3.38 mmol), methanol (20 mL) and potassiumcarbonate (1 g, 14.5 mmol) followed by flash column chromatography using7% ethyl acetate in hexane as the eluent, the title compound wasobtained (0.57 g, 80%) as a pale yellow solid.

¹H NMR (300 MHz, CDCl₃): δ 7.34 (d, 1H, J=2.5 Hz), 7.02 (d, 1H, J=2.5Hz), 3.19 (s, 1H), 2.83 (m, 1H), 2.74 (t, 2H, J=6.7 Hz), 1.97 (t, 2H,J=6.7 Hz), 1.35 (s, 6H), 1.03-0.86 (m, 2H), 0.66-0.61 (m, 2H).

3-[4-(4-Cyclopropyl-8,8-dimethyl-5-oxo-5,6,7,8-tetrahydro-naphthalen-2-ylethynyl)-phenyl]-acrylicacid ethyl ester Intermediate 161

Following General Procedure B and using8-cyclopropyl-4,4-dimethyl-6-ethynyl-1-tetralone (Intermediate 160, 0.1g, 0.42 mmol), (E)-3-(4-iodo-phenyl)-acrylic acid ethyl ester (0.13 g,0.42 mmol), triethyl amine (1 mL), copper(I)iodide (0.02 g, 0.1 mmol)and dichlorobis(triphenylphosphine)palladium(II) (0.070 g, 0.1 mmol)followed by flash column chromatography over silica gel (230-400 mesh),the title compound was obtained (0.12 g, 69%).

¹H NMR (300 MHz, CDCl₃): δ 7.65 (d, 1H, J=15.8 Hz), 7.52 (ABq, 4H, J=8.1Hz), 7.37 (d, 2H, J=1.5 Hz), 7.05 (d, 1H, J=1.5 Hz), 6.45 (d, 1H, J=15.8Hz), 4.26 (q, 2H, J=7.2 Hz), 2.88-2.79 (m, 1H), 2.77-2.71 (m, 2H),2.00-1.92 (m, 2H), 1.36-1.21 (m, 9H), 1.04-0.97 (m, 2H), 0.69-0.59 (m,2H).

3-{4-[4-Cyclopropyl-5-(cyclopropyl-methyl-amino)-8,8-dimethyl-5,6,7,8-tetrahydronaphthalen-2-ylethynyl]-phenyl}-acrylicacid ethyl ester Intermediate 162

Following General Procedure C and using3-[4-(4-cyclopropyl-8,8-dimethyl-5-oxo-5,6,7,8-tetrahydro-naphthalen-2-ylethynyl)-phenyl]-acrylicacid ethyl ester (Intermediate 161, 0.12 g, 0.29 mmol) indichloromethane (4 mL) and acetonitrile (2 mL), cyclopropyl amine (1 mL,14.5 mmol), acetic acid (1 mL) and sodium cyanoborohydride (0.16 g, 2.4mmol) followed by work up afforded an intermediate as an oil, that wasused as such for the next step. The residue (crude 0.18 g) was dissolvedin acetone (6 mL) and treated with potassium carbonate (0.28 g, 2 mmol)and methyl iodide (1 mL, 16 mmol). The resulting reaction mixture wasstirred at ambient temperature overnight. The volatiles were evaporatedin vacuo, the residue was diluted with water and extracted with diethylether (×2). The combined organic phase was dried over anhydrousmagnesium sulfate, filtered and evaporated to an oil. Flash columnchromatography over silica gel (230-400 mesh) followed by preparativenormal phase HPLC using 5% ethyl acetate in hexane as the mobile phaseafforded the title compound (0.08 g) as a clear oil, which was used assuch for the next step.

3-{4-[4-Cyclopropyl-5-(cyclopropyl-methyl-amino)-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-ylethynyl]-phenyl}-acrylicacid Compound 48

A solution of3-{4-[4-cyclopropyl-5-(cyclopropyl-methyl-amino)-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-ylethynyl]-phenyl}-acrylicacid ethyl ester (Intermediate 164, 0.08 g, 0.17 mmol) in methanol (3mL) and tetrahydrofuran (3 mL) was treated with 2M sodium hydroxidesolution (2 mL, 4 mmol) and the resulting reaction mixture was refluxedovernight. The reaction mixture was cooled to ambient temperature, thevolatiles were evaporated in vacuo, the residue was diluted withsaturated aqueous ammonium chloride solution, and extracted with ethylacetate (×2). The combined organic extract was dried over anhydroussodium sulfate, filtered and evaporated in vacuo to a solid. Preparativereverse phase HPLC using 10% water in acetonitrile as the mobile phaseafforded the title product as a solid (0.04 g, 50%).

¹H NMR (300 MHz, CDCl₃): δ 7.76 (d, 1H, J=15.8 Hz), 7.54 (Abq, 4H, J=8.8Hz), 7.38 (d, 1H, J=1.5 Hz), 6.96 (d, 1H, J=1.5 Hz), 6.47 (d, 1H, J=15.8Hz), 4.31 (t, 1H, J=4.7 Hz) 2.27 (s, 3H), 2.40-1.43 (m, 6H), 1.38 (s,3H), 1.23 (s, 3H), 0.98-0.78 (m, 4H), 0.39-0.13 (m, 4H).

8-Cyclopropyl-5-(cyclopropyl-methyl-amino)-4,4-dimethyl-(2-trimethylsilanyl)ethynyl-1,2,3,4-tetrahydronaphthaleneIntermediate 163

Following General Procedure C and using8-cyclopropyl-4,4-dimethyl-6-(trimethylsilanyl)ethynyl-3,4-dihydro-2H-naphthalen-1-one(Intermediate 159, 0.77 g, 2.5 mmol) in dichloromethane (6 mL) andacetonitrile (3 mL), cyclopropyl amine (3 mL, 45 mmol), acetic acid (1mL) and sodium cyanoborohydride (0.63 g, 9.5 mmol) followed by work upafforded an intermediate as an oil, that was used as such for the nextstep. The residue (crude 2.5 mmol) was dissolved in acetone (20 mL) andtreated with potassium carbonate (1.03 g, 7.5 mmol) and methyl iodide(1.55 mL, 25 mmol). The resulting reaction mixture was stirred atambient temperature over 2 days. The solids were filtered off, thefiltrate and washings were evaporated in vacuo to an oil. Flash columnchromatography over silica gel (230-400 mesh) using 2-4% ethyl acetatein hexane as the mobile phase afforded the title compound (0.58 g, 75%).

¹H NMR (300 MHz, CDCl₃): δ 7.31 (d, J=1.6 Hz, 1H), 6.89 (d, J=1.6 Hz,1H), 4.27 (br s, 1H), 2.40-2.30 (m, 1H), 2.30-2.20 (m, 1H), 2.24 (s,3H), 2.10-2.00 (m, 1H), 2.00-1.80 (m, 2H), 1.60-1.50 (m, 1H), 1.35 (s,3H), 1.20 (s, 3H), 0.90-0.75 (m, 4H), 0.40-0.25 (m, 3H), 0.26 (s, 9H),0.20-0.10 (m, 1H).

8-Cyclopropyl-5-(cyclopropyl-methyl-amino)-2-ethynyl-4,4-dimethyl-1,2,3,4-tetrahydronaphthaleneIntermediate 164

A solution of8-cyclopropyl-5-(cyclopropyl-methyl-amino)-4,4-dimethyl-(2-trimethylsilanyl)ethynyl-1,2,3,4-tetrahydronaphthalene(Intermediate 163, 0.3 g, 0.82 mmol) in methanol (10 mL) was treatedwith potassium carbonate (0.2 g, 1.44 mmol) and the resulting reactionmixture was stirred at ambient temperature overnight. The solids werefiltered off, the residue was diluted with water and extracted withdiethyl ether. The organic phase was dried over anhydrous magnesiumsulfate, filtered and evaporated to afford the title compound (0.22 g,92%).

¹H NMR (300 MHz, CDCl₃): δ 7.44 (d, J=1.6 Hz, 1H), 7.01 (d, J=1.6 Hz,1H), 4.38 (br s, 1H), 3.11 (s, 1H), 2.48-2.38 (m, 1H), 2.38-2.28 (m,1H), 2.34 (s, 3H), 2.18-2.08 (m, 1H), 2.05-1.85 (m, 2H), 1.70-1.60 (m,1H), 1.44 (s, 3H), 1.30 (s, 3H), 1.00-0.85 (m, 4H), 0.50-0.35 (m, 3H),0.30-0.18 (m, 1H).

2-{4-[4-Cyclopropyl-5-(cyclopropyl-methyl-amino)-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-ylethynyl]-phenyl}-propionicacid methyl ester Intermediate 165

Following General Procedure B and using8-cyclopropyl-5-(cyclopropyl-methyl-amino)-2-ethynyl-4,4-dimethyl-1,2,3,4-tetrahydronaphthalene(Intermediate 164, 0.11 g, 0.37 mmol), methyl-2-(4-iodophenyl)propionate (Reagent 1, 0.108 g, 0.37 mmol), triethyl amine (10mL), copper(I)iodide (0.019 g, 0.1 mmol) anddichlorobis(triphenylphosphine)palladium(II) (0.07 g, 0.1 mmol) followedby work up and flash column chromatography over silica gel (230-400mesh) using 1%-4% ethyl acetate in hexane as the eluent, the titlecompound was obtained as a pale yellow amorphous solid (0.148 g, 87%).

¹H NMR (300 MHz, CDCl₃): δ 7.51 (d, J=8.5 Hz, 2H), 7.39 (d, J=1.6 Hz,1H), 7.29 (d, J=8.5 Hz, 2H), 6.97 (d, J=1.6 Hz, 1H), 4.32 (bs, 1H), 3.75(q, J=7.0 Hz, 1H), 3.70 (s, 3H), 2.40-2.30 (m, 1H), 2.30-2.20 (m, 1H),2.28 (s, 3H), 2.18-2.08 (m, 1H), 2.02-1.82 (m, 2H), 1.62-1.52 (m, 1H),1.52 (d, J=7.0 Hz, 3H), 1.39 (s, 3H), 1.25 (s, 3H), 0.98-0.80 (m, 4H),0.45-0.25 (m, 3H), 0.20-0.15 (m, 1H).

2-{4-[4-Cyclopropyl-5-(cyclopropyl-methyl-amino)-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-ylethynyl]-phenyl}-propionicacid Compound 49

A solution of2-{4-[4-cyclopropyl-5-(cyclopropyl-methyl-amino)-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-ylethynyl]-phenyl}-propionicacid methyl ester (Intermediate 165, 0.075 g, 0.16 mmol) in methanol (2mL) and tetrahydrofuran (2 mL) was treated with 2M lithium hydroxide (1mL, 2 mmol) and the resulting reaction mixture was stirred at ambienttemperature for 5 h. The reaction mixture was neutralized with ammoniumchloride and extracted with ethyl acetate. The organic phase was washedwith water and brine, and dried over anhydrous sodium sulfate, filteredand evaporated in vacuo to afford the title product as a yellow solid(0.07 g, 96%).

¹H NMR (300 MHz, CDCl₃): δ 7.50 (d, J=8.5 Hz, 2H), 7.39 (d, J=1.6 Hz,1H), 7.31 (d, J=8.5 Hz, 2H), 6.97 (d, J=1.6 Hz, 1H), 4.34 (bs, 1H), 3.74(q, J=7.0 Hz, 1H), 2.40-2.30 (m, 1H), 2.30-2.20 (m, 1H), 2.29 (s, 3H),2.18-2.08 (m, 1H), 2.02-1.82 (m, 2H), 1.62-1.52 (m, 1H), 1.52 (d, J=7.0Hz, 3H), 1.39 (s, 3H), 1.24 (s, 3H), 0.98-0.80 (m, 4H), 0.40-0.30 (m,3H), 0.20-0.15 (m, 1H).

2-{4-[4-Cyclopropyl-5-(cyclopropyl-methyl-amino)-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-ylethynyl]-phenyl}-2-methyl-propionicacid methyl ester Intermediate 166

Following General Procedure B and using8-cyclopropyl-5-(cyclopropyl-methyl-amino)-2-ethynyl-4,4-dimethyl-1,2,3,4-tetrahydronaphthalene(Intermediate 164, 0.11 g, 0.37 mmol), methyl-2-(4-iodophenyl)-2-methyl-propionate (Reagent 2, 0.118 g, 0.39 mmol), triethylamine (10 mL), copper(I)iodide (0.019 g, 0.1 mmol) anddichlorobis(triphenylphosphine)palladium(II) (0.07 g, 0.1 mmol) followedby work up and flash column chromatography over silica gel (230-400mesh) using 1%-4% ethyl acetate in hexane as the eluent, the titlecompound was obtained as a pale yellow amorphous solid (0.125 g, 70%).

¹H NMR (300 MHz, CDCl₃): δ 7.51 (d, J=8.5 Hz, 2H), 7.39 (d, J=1.6 Hz,1H), 7.33 (d, J=8.5 Hz, 2H), 6.97 (d, J=1.6 Hz, 1H), 4.32 (bs, 1H), 3.68(s, 3H), 2.40-2.30 (m, 1H), 2.30-2.20 (m, 1H), 2.28 (s, 3H), 2.15-2.05(m, 1H), 2.00-1.80 (m, 2H), 1.61 (s, 6H), 1.62-1.52 (m, 1H), 1.39 (s,3H), 1.25 (s, 3H), 0.95-0.80 (m, 4H), 0.45-0.30 (m, 3H), 0.20-0.10 (m,1H).

2-{4-[4-Cyclopropyl-5-(cyclopropyl-methyl-amino)-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-ylethynyl]-phenyl}-2-methyl-propionicacid Compound 50

A solution of2-{4-[4-cyclopropyl-5-(cyclopropyl-methyl-amino)-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-ylethynyl]-phenyl}-2-methyl-propionicacid methyl ester (Intermediate 166, 0.125 g, 0.266 mmol) in methanol(2.5 mL) and tetrahydrofuran (2.5 mL) was treated with 3M potassiumhydroxide (1 mL, 3 mmol) and the resulting reaction mixture was stirredat ambient temperature overnight. The reaction mixture was neutralizedwith ammonium chloride and extracted with ethyl acetate. The organicphase was washed with water and brine, and dried over anhydrous sodiumsulfate, filtered and evaporated in vacuo to afford the title product asan amorphous pale yellow solid (0.12 g, 98%).

¹H NMR (300 MHz, CDCl₃): δ 7.51 (d, J=8.5 Hz, 2H), 7.40-7.38 (m, 3H),6.97 (d, J=1.6 Hz, 1H), 4.33 (bs, 1H), 2.40-2.30 (m, 1H), 2.30-2.20 (m,1H), 2.28 (s, 3H), 2.10-2.00 (m, 1H), 2.00-1.80 (m, 2H), 1.62 (s, 6H),1.60-1.50 (m, 1H), 1.39 (s, 3H), 1.24 (s, 3H), 0.95-0.80 (m, 4H),0.45-0.30 (m, 3H), 0.20-0.10 (m, 1H).

Cyclopropyl-(4,4-dimethyl-6-trimethylsilanylethynyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-methyl-amineIntermediate 167

Following General Procedure C and using4,4-dimethyl-6-trimethylsilanylethynyl-3,4-dihydro-2H-naphthalen-1-one(described in U.S. Pat. No. 6,252,090, 1.23 g, 4.6 mmol) indichloromethane (7 mL) and acetonitrile (3 mL), cyclopropyl amine (2.5mL, 36 mmol), acetic acid (2.5 mL) and sodium cyanoborohydride (0.58 g,8.6 mmol) followed by work up and flash column chromatography oversilica gel (230-400 mesh) using 8% ethyl acetate in hexane as the eluentafforded an intermediate as a golden yellow solid (1.07 g, 76%). Theintermediate (0.67 g, 2.62 mmol) was dissolved in acetone (10 mL) andtreated with potassium carbonate (2.2 g, 16 mmol) and methyl iodide(0.75 mL, 12 mmol). The resulting reaction mixture was stirred atambient temperature overnight. The volatiles were evaporated in vacuo,the residue was diluted with water and extracted with diethyl ether. Theorganic phase was dried over anhydrous magnesium sulfate, filtered andevaporated to an oil which was used as such for the next step.

Cyclopropyl-(6-ethynyl-4,4-dimethyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-methyl-amineIntermediate 168

A solution ofcyclopropyl-(4,4-dimethyl-6-trimethylsilanylethynyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-methyl-amine(Intermediate 167, 0.67 g, 2.62 mmol) in methanol (10 mL) was treatedwith potassium carbonate (1 g, 7.23 mmol) and the resulting reactionmixture was stirred at ambient temperature overnight. The volatiles wereevaporated in vacuo and the residue was diluted with water and extractedwith diethyl ether. The organic extract was dried over anhydrousmagnesium sulfate, filtered and evaporated in vacuo to afford the titleproduct as a light yellow oil (0.5 g, 75%).

¹H NMR (300 MHz, CDCl₃): δ 7.47 (d, 1H, J=8.2 Hz), 7.41 (d, 1H, J=1.4Hz), 6.79 (dd, 1H, J=8.2, 1.4 Hz), 3.92 (t, 1H, J=8.2 Hz), 3.01 (s, 3H),2.11 (s, 3H), 2.15-2.07 (m, 1H), 1.95-1.57 (m, 4H), 1.29 (s, 3H), 1.24(s, 3H), 0.53-0.37 (m, 4H).

2-{4-[5-(Cyclopropyl-methyl-amino)-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-ylethynyl]-phenyl}-propionicacid methyl ester Intermediate 169

Following General Procedure B and using5-(cyclopropyl-methyl-amino)-2-ethynyl-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalene(Intermediate 168, 0.116 g, 0.46 mmol),methyl-2-(4-iodophenyl)propionate (Reagent 1, 0.17 g, 0.59 mmol),triethyl amine (0.75 mL), copper(I)iodide (0.07 g, 0.37 mmol) andtetrakis(triphenylphosphine)palladium(0) (0.022 g, 0.019 mmol) followedby flash column chromatography over silica gel (230-400 mesh) andpreparative normal phase HPLC using 5% ethyl acetate in hexane as theeluent, the title compound was obtained (0.08 g, 42%).

¹H NMR (300 MHz, CDCl₃): δ 7.51-7.43 (m, 3H), 7.29-7.22 (m, 4H), 3.94(t, 1H, J=7.9 Hz), 3.76-3.62 (m, 1H), 3.65 (s, 3H), 2.12 (s, 3H),2.15-2.08 (m, 1H), 2.00-1.54 (2m, 4H), 1.52-1.46 (2d, 3H, J=7.4 Hz),1.31 (s, 3H), 1.27 (s, 3H), 0.53-0.38 (m, 4H).

2-{4-[5-(Cyclopropyl-methyl-amino)-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-ylethynyl]-phenyl}-propionicacid Compound 51

A solution of2-{4-[5-(cyclopropyl-methyl-amino)-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-ylethynyl]-phenyl}-propionicacid methyl ester (Intermediate 169, 0.022 g, 0.05 mmol) in methanol (2mL) and tetrahydrofuran (2 mL) was treated with a 2M solution of sodiumhydroxide (1 mL, 2 mmol) and the resulting reaction mixture was stirredat ambient temperature overnight. The reaction mixture was neutralizedwith saturated aqueous ammonium chloride solution and extracted withethyl acetate. The organic phase was washed with water and brine, anddried over anhydrous magnesium sulfate, filtered and evaporated in vacuoto a residue that was subjected to preparative reverse phase HPLC using10% water in acetonitrile as the mobile phase to afford the titleproduct (0.008 g, 40%).

¹H NMR (300 MHz, CDCl₃): δ 7.50-7.44 (m, 3H), 7.31-7.27 (m, 3H), 7.20(dd, 1H, J=8.2, 1.5 Hz), 4.00 (t, 11, J=8.2 Hz), 3.74 (q, 1H, J=7.1 Hz),1H), 2.15 (s, 3H), 2.15-2.10 (m, 1H), 1.98-1.81 (m, 2H), 1.80-1.63 (m,2H), 1.51 (d, 3H, J=7.1 Hz), 1.31 (s, 3H), 1.27 (s, 3H), 0.52-0.49 (m,4H).

2-{4-[5-(Cyclopropyl-methyl-amino)-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-ylethynyl]-phenyl}-2-methyl-propionicacid methyl ester Intermediate 170

Following General Procedure B and using5-(cyclopropyl-methyl-amino)-2-ethynyl-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalene(Intermediate 168, 0.16 g, 0.63 mmol),methyl-2-(4-iodophenyl)-2-methyl-propionate (Reagent 2, 0.18 g, 0.58mmol), triethyl amine (3 mL), copper(I)iodide (0.048 g, 0.25 mmol) andtetrakis(triphenylphosphine)palladium(0) (0.032 g, 0.027 mmol) followedby flash column chromatography over silica gel (230-400 mesh) andpreparative normal phase HPLC using 6% ethyl acetate in hexane as themobile phase, the title compound was obtained (0.14 g, 56%).

¹H NMR (300 MHz, CDCl₃): δ 7.54-7.47 (m, 4H), 7.34-7.26 (m, 3H), 3.97(t, 1H, J=7.9 Hz), 3.68 (s, 3H), 2.16 (s, 3H), 2.16-2.00 (m, 1H),2.00-1.61 (2m, 4H), 1.61 (s, 6H), 1.35 (s, 3H), 1.30 (s, 3H), 0.56-0.44(m, 4H).

2-{4-[5-(Cyclopropyl-methyl-amino)-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-ylethynyl]-phenyl}-2-methyl-propionicacid Compound 52

A solution of2-{4-[5-(cyclopropyl-methyl-amino)-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-ylethynyl]-phenyl}-2-methyl-propionicacid methyl ester (Intermediate 170, 0.08 g, 0.19 mmol) in methanol (3mL) and tetrahydrofuran (3 mL) was treated with a 2M solution of sodiumhydroxide (2 mL, 4 mmol) and the resulting reaction mixture was refluxedovernight. The volatiles were evaporated in vacuo and the residue wasdiluted with saturated aqueous ammonium chloride solution and extractedwith ethyl acetate. The organic phase was dried over anhydrous magnesiumsulfate, filtered and evaporated in vacuo to afford the title product(0.07 g, ˜100%).

¹H NMR (300 MHz, CDCl₃): δ 9.47 (br s, 1H), 7.53-7.49 (m, 4H), 7.39 (d,2H, J=8.5 Hz), 7.26 (dd, 1H, J=7.9, 1.5 Hz), 3.97 (t, 1H, J=7.9 Hz),2.16 (s, 3H), 2.16-2.00 (m, 1H), 2.00-1.61 (2m, 4H), 1.61 (s, 6H), 1.35(s, 3H), 1.30 (s, 3H), 0.56-0.44 (m, 4H).

6-Hydroxy-4,4,7-trimethyl-3,4-dihydro-2H-naphthalen-1-one Intermediate171

A solution of 6-methoxy-4,4,7-trimethyl-3,4-dihydro-2H-naphthalen-1-one(described in U.S. 2003/0166932, published Sep. 4, 2003, incorporatedherein by reference; 5.5 g, 25.6 mmol) and sodium cyanide (6.25 g, 127mmol) in anhydrous dimethylsulfoxide (100 mL) was heated at 230° C. for48 h under argon. The reaction mixture was then cooled to ambienttemperature, poured into ice and acidified (Caution! Hydrogen cyanideevolution!) with dilute hydrochloric acid and extracted with ethylacetate (×2). The combined organic extract was washed with brine (×1),dried over anhydrous sodium sulfate, filtered and evaporated to affordthe title compound, which was used as such for the next step (5.2 g,˜100%).

¹H NMR (300 MHz, CDCl₃): δ 7.86 (s, 1H), 6.87 (s, 1H), 2.70 (t, 2H,J=7.0 Hz), 2.24 (s, 3H), 1.97 (t, 2H, J=7.0 Hz), 1.32 (s, 6H).

Trifluoro-methanesulfonic acid3,8,8-trimethyl-5-oxo-5,6,7,8-tetrahydro-naphthalen-2-yl esterIntermediate 172

A solution of 6-hydroxy-4,4,7-trimethyl-3,4-dihydro-2H-naphthalen-1-one(Intermediate 171, 5.2 g, 25.6 mmol) and 4-dimethylaminopyridine (6.1 g,50 mmol) in anhydrous dichloromethane (50 mL) was treated withN-phenyltrifluoromethanesulfonimide (9.54 g, 26.7 mmol) under argon andstirred at ambient temperature for 1 h. The reaction mixture wassubjected to flash column chromatography on silica gel (230-400 mesh)using 6-7% ethyl acetate in hexane as the eluent to afford the titlecompound (6.4 g, 75%).

¹H NMR (300 MHz, CDCl₃): δ 7.96 (s, 1H), 7.28 (s, 1H), 2.74 (t, 2H,J=7.0 Hz), 2.37 (s, 3H), 2.04 (t, 2H, J=7.0 Hz), 1.39 (s, 6H).

4,4,7-Trimethyl-6-trimethylsilanylethynyl-3,4-dihydro-2H-naphthalen-1-oneIntermediate 173

Following General Procedure D and using trifluoro-methanesulfonic acid3,8,8-trimethyl-5-oxo-5,6,7,8-tetrahydro-naphthalen-2-yl ester(Intermediate 172, 5.04 g, 15 mmol), triethyl amine (20 mL),copper(I)iodide (0.6 g, 3 mmol), trimethylsilyl acetylene (5.3 mL, 37.5mmol) and dichlorobis(triphenylphosphine)palladium(II) (2.2 g, 3 mmol)followed by flash column chromatography over silica gel (230-400 mesh)using 6% ethyl acetate in hexane as the eluent, the title compound (4 g,93%) was obtained as a pale yellow solid.

¹H NMR (300 MHz, CDCl₃): δ 7.54 (s, 1H), 7.19 (s, 1H), 2.42 (t, 2H,J=7.0 Hz), 2.14 (s, 3H), 1.70 (t, 2H, J=7.0 Hz), 1.08 (s, 6H), 0.00 (s,9H).

Cyclopropyl-(6-ethynyl-4,4,7-trimethyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-methyl-amineIntermediate 174

Following General Procedure C and using4,4,7-trimethyl-6-trimethylsilanylethynyl-3,4-dihydro-2H-naphthalen-1-one(Intermediate 173, 4 g, 14 mmol) in dichloromethane (30 mL) andacetonitrile (10 mL), cyclopropyl amine (3.11 mL, 45 mmol), acetic acid(3.2 mL) and sodium cyanoborohydride (2 g, 30 mmol) followed by work upand flash column chromatography over silica gel (230-400 mesh) using 10%ethyl acetate in hexane as the eluent afforded an intermediate as a paleyellow solid, that was used as such for the next step (4.1 g, 90%). Theintermediate (4.1 g, 13 mmol) was dissolved in acetone (40 mL) andtreated with potassium carbonate (10 g, 72 mmol) and methyl iodide (2.5mL, 40 mmol). The resulting reaction mixture was stirred at ambienttemperature overnight. The volatiles were evaporated in vacuo, theresidue was dissolved in methanol (100 mL) and treated with potassiumcarbonate (10 g, 72 mmol) and the resulting reaction mixture was stirredat ambient temperature for 1.5 h. The volatiles were evaporated invacuo, the residue was diluted with water and extracted with diethylether (×2). The combined organic phase was dried over anhydrousmagnesium sulfate, filtered and evaporated to an oil that was filteredover a short plug of silica gel (230-400 mesh) to afford the titlecompound (3.2 g, 92%) as a clear oil.

¹H NMR (300 MHz, CDCl₃): δ 7.42 (s, 1H), 7.38 (s, 1H), 3.49 (t, 1H,J=7.0 Hz), 3.23 (s, 1H), 2.40 (s, 3H), 2.15 (s, 3H), 2.15-2.10 (m, 1H),1.97-1.62 (2m, 4H), 1.30 (s, 3H), 1.26 (s, 3H), 0.56-0.28 (m, 4H).

2-{4-[5-(Cyclopropyl-methyl-amino)-3,8,8-trimethyl-5,6,7,8-tetrahydro-naphthalen-2-ylethynyl]-phenyl}-2-methyl-propionicacid methyl ester Intermediate 175

Following General Procedure B and usingcyclopropyl-(6-ethynyl-4,4,7-trimethyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-methyl-amine(Intermediate 174, 0.1 g, 0.29 mmol),methyl-2-(4-iodophenyl)-2-methyl-propionate (Reagent 2, 0.09 g, 0.29mmol), triethyl amine (8 mL), copper(I)iodide (0.019 g, 0.1 mmol) anddichlorobis(triphenylphosphine)palladium(II) (0.07 g, 0.1 mmol) followedby flash column chromatography over silica gel (230-400 mesh) using 1-2%ethyl acetate in hexane as the eluent, the title compound was obtained(0.035 g, 26%).

¹H NMR (300 MHz, CDCl₃): δ 7.49 (d, J=8.5 Hz, 2H), 7.41 (s, 1H), 7.38(d, J=8.5 Hz, 2H), 7.32 (s, 1H), 3.92 (m, 1H), 3.67 (s, 3H), 2.43 (s,3H), 2.18-2.10 (m, 1H), 2.14 (s, 3H), 1.98-1.85 (m, 2H), 1.80-1.64 (m,2H), 1.60 (s, 6H), 1.31 (s, 3H), 1.26 (s, 3H), 0.58-0.42 (m, 4H).

2-{4-[5-(Cyclopropyl-methyl-amino)-3,8,8-trimethyl-5,6,7,8-tetrahydro-naphthalen-2-ylethynyl]-phenyl}-2-methyl-propionicacid Compound 53

A solution of2-{4-[5-(cyclopropyl-methyl-amino)-3,8,8-trimethyl-5,6,7,8-tetrahydro-naphthalen-2-ylethynyl]-phenyl}-2-methyl-propionicacid methyl ester (Intermediate 175, 0.035 g, 0.08 mmol) in methanol (2mL) and tetrahydrofuran (2 mL) was treated with a 2M solution of sodiumhydroxide (2 mL, 4 mmol) and the resulting reaction mixture was refluxedfor 2 days. The volatiles were evaporated in vacuo and the residue wasneutralized with 5% aqueous hydrochloric acid and extracted with ethylacetate. The organic phase was washed with water and brine, dried overanhydrous sodium sulfate, filtered and evaporated in vacuo to a residuethat was purified by preparative reverse phase HPLC using 10% water inacetonitrile as the mobile phase to afford the title product (0.022 g,64%).

¹H NMR (300 MHz, CDCl₃): δ 7.48 (d, J=8.5 Hz, 2H), 7.41 (s, 1H),7.37-7.34 (m, 3H), 3.95 (m, 1H), 2.40 (s, 3H), 2.18-2.10 (m, 1H), 2.14(s, 3H), 1.98-1.85 (m, 2H), 1.80-1.64 (m, 2H), 1.57 (s, 6H), 1.29 (s,3H), 1.25 (s, 3H), 0.56-0.42 (m, 4H).

8-Ethyl-4,4-dimethyl-6-methoxy-3,4-dihydro-2H-naphthalen-1-oneIntermediate 176

A solution of8-vinyl-6-methoxy-4,4-dimethyl-3,4-dihydro-2H-naphthalen-1-one(Intermediate 155, 1.12 g, 4.86 mmol) in ethyl acetate (10 mL) wastreated with 10% palladium on carbon (100 mg) and the resulting reactionmixture was stirred under an atmosphere of hydrogen overnight. Thereaction mixture was filtered over a bed of celite and the filtrate wasevaporated to afford the title product (1.1 g, 98%).

¹H NMR (300 MHz, CDCl₃): δ 6.77 (d, 1H, J=2.6 Hz), 6.54 (d, 1H, J=2.6Hz), 3.87 (s, 3H), 3.05 (q, 2H, J=7.3 Hz), 2.67 (t, 2H, J=6.7 Hz), 1.95(t, 2H, J=6.7 Hz), 1.36 (s, 6H), 1.23 (t, 3H, J=7.3 Hz).

8-Ethyl-6-hydroxy-4,4-dimethyl-3,4-dihydro-2H-naphthalen-1-oneIntermediate 177

A solution of8-ethyl-4,4-dimethyl-6-methoxy-3,4-dihydro-2H-naphthalen-1-one(Intermediate 176, 1.1 g, 4.73 mmol) and sodium cyanide (1.6 g, 33 mmol)in anhydrous dimethylsulfoxide (20 mL) was heated at 210° C. overnightunder argon. The reaction mixture was then cooled to ambienttemperature, poured into ice and acidified (Caution! Hydrogen cyanideevolution!) using 10% hydrochloric acid and extracted with ethylacetate. The combined organic extract was washed with brine (×1), driedover anhydrous sodium sulfate, filtered and evaporated to afford a darkorange solid.

Flash column chromatography on silica gel (230-400 mesh) using 10-20%ethyl acetate in hexane as the eluent afforded the title compound as ayellow solid (0.82 g, 82%).

¹H NMR (300 MHz, CD₃COCD₃): δ 8.99 (s, 1H), 6.81 (d, 1H, J=2.6 Hz), 6.64(d, 1H, J=2.6 Hz), 2.99 (q, 2H, J=7.3 Hz), 2.60 (t, 21-1, J=6.7 Hz),1.93 (t, 2H, J=6.7 Hz), 1.34 (s, 6H), 1.17 (t, 3H, J=7.3 Hz).

Trifluoro-methanesulfonic acid4-ethyl-8,8-dimethyl-5-oxo-5,6,7,8-tetrahydro-naphthalen-2yl esterIntermediate 178

A solution of8-ethyl-6-hydroxy-4,4-dimethyl-3,4-dihydro-2H-naphthalen-1-one(Intermediate 177, 0.27 g, 1.24 mmol) and 4-dimethylaminopyridine (0.242g, 1.98 mmol) in anhydrous dichloromethane (10 mL) was treated with2-[N,N-bis(trifluoromethylsulfonyl)amino]-5-chloro-pyridine (0.58 g,1.48 mmol) under argon at ambient temperature for 5 h. The reactionmixture was subjected to flash column chromatography on silica gel(230-400 mesh) using 5% ethyl acetate in hexane as the eluent to affordthe title compound (0.43 g, 98%).

¹H NMR (300 MHz, CDCl₃): δ 7.15 (d, 1H, J=2.6 Hz), 7.04 (d, 1H, J=2.6Hz), 3.05 (q, 2H, J=7.3 Hz), 2.74 (t, 2H, J=6.7 Hz), 2.00 (t, 2H, J=6.7Hz), 1.38 (s, 6H), 1.24 (t, 3H, J=7.3 Hz).

8-Ethyl-4,4-dimethyl-6-(trimethylsilanylethynyl-3,4-dihydro-2H-naphthalen-1-oneIntermediate 179

Following General Procedure D and using trifluoro-methanesulfonic acid4-ethyl-8,8-dimethyl-5-oxo-5,6,7,8-tetrahydro-naphthalen-2yl ester(Intermediate 178, 0.9 g, 2.57 mmol), triethyl amine (6 mL), anhydrousN,N-dimethylformamide (5 mL),dichlorobis(triphenylphosphine)palladium(II) (0.144 g, 0.2 mmol) and(trimethylsilyl)acetylene (2 mL, 13.64 mmol), the reaction was conductedovernight in a sealed tube at 90° C. Work-up followed by flash columnchromatography over silica gel (230-400 mesh) using 2-3% ethyl acetatein hexane as the eluent to afforded the title compound as an orange oil(0.82 g, quantitative).

¹H NMR (300 MHz, CDCl₃): δ 7.34 (d, 1H, J=1.5 Hz), 7.21 (d, 1H, J=1.5Hz), 2.97 (q, 2H, J=7.6 Hz), 2.69 (t, 2H, J=6.7 Hz), 1.95 (t, 2H, J=6.7Hz), 1.35 (s, 6H), 1.20 (t, 3H, J=7.6 Hz), 0.27 (s, 9H).

8-Ethyl-6-ethynyl-4,4-dimethyl-3,4-dihydro-2H-naphthalen-1-oneIntermediate 180

Following General Procedure F and using8-ethyl-4,4-dimethyl-6-(trimethylsilanyl)ethynyl-3,4-dihydro-2H-naphthalen-1-one(Intermediate 179, 0.66 g, 2.2 mmol), methanol (10 mL) and potassiumcarbonate (0.4 g, 2.9 mmol) the title compound was obtained as an orangeoil (0.59 g, 100%). ¹H NMR (300 MHz, CDCl₃): δ 7.51 (d, 1H, J=1.51 Hz),7.37 (d, 1H, J=1.5 Hz), 3.32 (s, 1H), 3.10 (q, 2H, J=7.3 Hz), 2.84 (t,2H, J=6.7 Hz), 2.08 (t, 2H, J=6.7 Hz), 1.48 (s, 6H), 1.33 (t, 3H, J=7.3Hz).

2-[4-(4-Ethyl-8,8-dimethyl-5-oxo-5,6,7,8-tetrahydro-naphthalen-2-ethynyl)-phenyl]-2-methyl-propionicacid methyl ester Intermediate 181

Following General Procedure B and using8-ethyl-6-ethynyl-4,4-dimethyl-3,4-dihydro-2H-naphthalen-1-one(Intermediate 180, 0.09 g, 0.39 mmol), methyl-2-(4-iodophenyl)-2-methyl-propionate (Reagent 2, 0.152 g, 0.5 mmol), triethylamine (8 mL), copper(I)iodide (0.024 g, 0.12 mmol) anddichlorobis(triphenylphosphine)palladium(II) (0.087 g, 0.12 mmol)followed by flash column chromatography over silica gel (230-400 mesh)using 2-10% ethyl acetate in hexane as the eluent, the title compoundwas obtained as an oil (0.095 g, 59%).

¹H NMR (300 MHz, CDCl₃): δ 7.53 (d, J=8.8 Hz, 2H), 7.43 (d, J=1.8 Hz,1H), 7.35 (d, J=8.8 Hz, 2H), 7.30 (d, J=1.8 Hz, 1H), 3.68 (s, 3H), 3.03(q, J=7.3 Hz, 2H), 2.73 (t, J=6.9 Hz, 2H), 1.99 (t, J=6.9 Hz, 2H), 1.61(s, 6H), 1.40 (s, 6H), 1.25 (t, J=7.3 Hz, 3H).

2-{4-[5-(Cyclopropyl-methyl-amino)-4-ethyl-8,8-dimethyl-5,6,7,8-tetrahydronaphthalen-2-ylethynyl]-phenyl}-2-methyl-propionicacid methyl ester Intermediate 182

Following General Procedure C and using2-[4-(4-ethyl-8,8-dimethyl-5-oxo-5,6,7,8-tetrahydro-naphthalen-2-ylethynyl)-phenyl]-2-methyl-propionicacid methyl ester (Intermediate 181, 0.095 g, 0.23 mmol) indichloromethane (3 mL) and acetonitrile (1.5 mL), cyclopropyl amine (1mL, 14.5 mmol), acetic acid (1 mL) and sodium cyanoborohydride (0.12 g,1.91 mmol) followed by work up afforded an intermediate as an oil, thatwas used as such for the next step. The intermediate (crude 0.23 mmol,0.13 g) was dissolved in acetone (6 mL) and treated with potassiumcarbonate (0.23 g, 1.66 mmol) and methyl iodide (1.5 mL, 25 mmol). Theresulting reaction mixture was stirred at ambient temperature overnight.The solids were filtered off, the filtrate and washings were evaporatedin vacuo to an oil. Flash column chromatography over silica gel (230-400mesh) using 5-10% ethyl acetate in hexane as the eluent afforded thetitle compound (0.07, 65%).

¹H NMR (300 MHz, CDCl₃): δ 7.55 (d, J=8.8 Hz, 2H), 7.43 (d, J=1.7 Hz,1H), 7.37 (d, J=8.8 Hz, 2H), 7.22 (d, J=1.7 Hz, 1H), 4.13 (m, 1H), 3.72(s, 3H), 2.78-2.68 (m, 2H), 2.32-2.24 (m, 1H), 2.25 (s, 3H), 2.18-2.08(m, 1H), 1.99-1.79 (m, 2H), 1.65 (s, 6H), 1.63-1.53 (m, 1H), 1.42 (s,3H), 1.29 (s, 3H), 1.23 (t, J=7.3 Hz, 3H), 0.50-0.40 (m, 3H), 0.30-0.20(m, 11-1).

2-{4-[5-(Cyclopropyl-methyl-amino)-4-ethyl-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-ylethynyl]-phenyl}-2-methyl-propionicacid Compound 54

A solution of2-{4-[5-(cyclopropyl-methyl-amino)-4-ethyl-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-ylethynyl]-phenyl}-2-methyl-propionicacid methyl ester (Intermediate 182, 0.035 g, 0.076 mmol) in methanol (3mL) and tetrahydrofuran (2 mL) was treated with 3M potassium hydroxide(2 mL, 4 mmol) and the resulting reaction mixture was heated at 80° C.for 2 days. The reaction mixture was neutralized with ammonium chlorideand extracted with ethyl acetate. The organic phase was washed withwater and brine, and dried over anhydrous sodium sulfate, filtered andevaporated in vacuo to afford a residue that was purified by preparativereverse phase HPLC to afford the title product (0.023 g, 69%).

¹H NMR (300 MHz, CDCl₃): δ 7.49 (d, J=8.4 Hz, 2H), 7.36-7.26 (m, 3H),7.16 (d, J=1.7 Hz, 1H), 4.06 (m, 1H), 2.71-2.63 (m, 2H), 2.25-2.17 (m,1H), 2.18 (s, 3H), 2.05-2.00 (m, 1H), 1.95-1.78 (m, 2H), 1.60-1.50 (m,1H), 1.58 (s, 6H), 1.35 (s, 3H), 1.22 (s, 3H), 1.16 (t, 0.1=7.3 Hz, 3H),0.4-0.3 (m, 3H), 0.2-0.1 (m, 1H).

Trifluoro-methanesulfonic acid4,4,7-trimethyl-6-trimethylsilanylethynyl-3,4-dihydro-naphthalen-1-ylester Intermediate 183

A stirred, cooled (−78° C.) solution of4,4,7-trimethyl-6-trimethylsilanylethynyl-3,4-dihydro-2H-naphthalen-1-one(Intermediate 173, 0.95 g, 3.33 mmol) in anhydrous tetrahydrofuran (10mL) under argon was treated with a 1M solution of sodiumbis(trimethylsilyl)amide in tetrahydrofuran (5 mL, 5 mmol). After 1 h,N-phenyltrifluoromethanesulfonimide (1.08 g, 3.33 mmol) was added andthe reaction mixture was stirred at ambient temperature for 1 h. Thereaction was quenched with saturated aqueous ammonium chloride solution,diluted with water and extracted with diethyl ether (×2). The combinedorganic extract was dried over anhydrous magnesium sulfate, filtered andevaporated in vacuo to a residue that was subjected to flash columnchromatography on silica gel using 2-4% ethyl acetate in hexane as theeluent to afford the title compound (0.73 g, 52%).

¹H NMR (300 MHz, CDCl₃): δ 7.08 (s, 1H), 6.92 (s, 1H), 5.67 (t, 2H,J=5.0 Hz), 2.15 (s, 3H), 2.08 (d, 2H, J=5.0 Hz), 1.00 (s, 6H), 0.00 (s,9H).

4,4,7-Trimethyl-6-trimethylsilanylethynyl-3,4-dihydro-naphthalene-1-carboxylicacid ethyl ester Intermediate 184

Following General Procedure E and using trifluoro-methanesulfonic acid4,4,7-trimethyl-6-trimethylsilanylethynyl-3,4-dihydro-naphthalen-1-ylester (Intermediate 183, 0.73 g, 1.75 mmol), palladium acetate (0.1 g,0.45 mmol), 1,3-bis(diphenylphosphino)propane (0.1 g, 0.24 mmol),N,N-dimethylformamide (3.5 mL), ethanol (3.5 mL) and triethyl amine (3.5mL) followed by flash column chromatography over silica gel (230-400mesh) using 5-10% ethyl acetate in hexane as the eluent the titlecompound was obtained (0.435 g, 73%).

¹H NMR (300 MHz, CDCl₃): δ 7.42 (s, 1H), 7.10 (s, 1H), 6.76 (t, 2H,J=5.0 Hz), 4.04 (q, 2H, J=7.0 Hz), 2.15 (s, 3H), 2.02 (d, 2H, J=5.0 Hz),1.09 (t, 3H, J=7.0 Hz), 0.97 (s, 6H), 0.00 (s, 9H).

6-Ethynyl-4,4,7-trimethyl-3,4-dihydro-naphthalene-1-carboxylic acidethyl ester Intermediate 185

Following General Procedure F and using4,4,7-trimethyl-6-trimethylsilanylethynyl-3,4-dihydro-naphthalene-1-carboxylicacid ethyl ester (Intermediate 184, 0.43 g, 1.3 mmol), ethanol (4 mL)and potassium carbonate (0.84 g, 6.06 mmol), the title compound wasobtained (0.33 g, 95%).

¹H NMR (300 MHz, CDCl₃): δ 7.70 (s, 1H), 7.40 (s, 1H), 7.05 (t, 2H,J=5.0 Hz), 4.30 (q, 2H, J=7.0 Hz), 2.43 (s, 3H), 2.30 (d, 2H, J=5.0 Hz),1.36 (t, 3H, J=7.0 Hz), 1.23 (s, 6H).

6-(4-Methoxycarbonylmethyl-phenylethynyl)-4,4,7-trimethyl-3,4-dihydro-naphthalene-1-carboxylicacid ethyl ester Intermediate 186

Following General Procedure B and using6-ethynyl-4,4,7-trimethyl-3,4-dihydro-naphthalene-1-carboxylic acidethyl ester (Intermediate 185, 0.126 g, 0.47 mmol), 4-iodo phenyl aceticacid methyl ester (0.13 g, 0.47 mmol), triethyl amine (2 mL),copper(I)iodide (0.029 g, 0.15 mmol) anddichlorobis(triphenylphosphine)palladium(II) (0.07 g, 0.1 mmol) followedby flash column chromatography over silica gel (230-400 mesh) using10-12% ethyl acetate in hexane as the eluent, the title compound wasobtained as a viscous oil (0.144 g, 74%).

¹H NMR (300 MHz, CDCl₃): δ 7.72 (s, 1H), 7.47 (d, 2H, J=8.1 Hz), 7.35(s, 1H), 7.27 (d, 2H, J=8.1 Hz), 7.05 (t, 2H, J=5.0 Hz), 4.34 (q, 2H,J=7.0 Hz), 3.70 (s, 3H), 3.64 (s, 2H), 2.48 (s, 3H), 2.32 (d, 2H, J=5.0Hz), 1.38 (t, 3H, J=7.0 Hz), 1.27 (s, 6H).

6-(4-Carboxymethyl-phenylethynyl)-4,4,7-trimethyl-3,4-dihydro-naphthalene-1-carboxylicacid ethyl ester Compound 55

A solution of6-(4-carboxymethyl-phenylethynyl)-4,4,7-trimethyl-3,4-dihydronaphthalene-1-carboxylicacid ethyl ester (Intermediate 186, 0.144 g, 0.35 mmol) in ethanol (2mL) was treated with a 1M solution of lithium hydroxide (1 mL, 1 mmol)and the resulting reaction mixture was stirred at ambient temperaturefor 3 h. The volatiles were evaporated in vacuo, the residue wasneutralized with saturated aqueous ammonium chloride solution andextracted with diethyl ether and ethyl acetate. The organic phase wasdried over anhydrous magnesium sulfate, filtered and evaporated in vacuoto a residue that was purified by preparative reverse phase HPLC using10% water in acetonitrile as the mobile phase to afford the titleproduct (0.071 g, 50%).

¹H NMR (300 MHz, CDCl₃): δ 7.68 (s, 1H), 7.47 (br d, 2H, J=8.1 Hz), 7.41(s, 1H), 7.21 (br d, 2H), 7.04 (t, 2H, J=5.0 Hz), 4.31 (q, 2H, J=7.0Hz), 3.65 (br s, 2H), 2.46 (s, 3H), 2.30 (d, 2H, J=5.0 Hz), 1.37 (t, 3H,J=7.0 Hz), 1.24 (s, 6H).

6-(3-Fluoro-4-methoxycarbonylmethyl-phenylethynyl)-4,4,7-trimethyl-3,4-dihydronaphthalene-1-carboxylicacid ethyl ester Intermediate 187

Following General Procedure B and using6-ethynyl-4,4,7-trimethyl-3,4-dihydro-naphthalene-1-carboxylic acidethyl ester (Intermediate 185, 0.2 g, 0.75 mmol), 2-fluoro-4-iodo phenylacetic acid methyl ester (0.22 g, 0.75 mmol), triethyl amine (2 mL),copper(I)iodide (0.03 g, 0.16 mmol) anddichlorobis(triphenylphosphine)palladium(II) (0.1 g, 0.14 mmol) followedby flash column chromatography over silica gel (230-400 mesh) using10-12% ethyl acetate in hexane as the eluent, the title compound wasobtained as a viscous oil (0.23 g, 73%).

¹H NMR (300 MHz, CDCl₃): δ 7.73 (s, 1H), 7.42 (s, 1H), 7.30-7.20 (m,3H), 7.06 (t, 2H, J=5.0 Hz), 4.32 (q, 2H, J=7.0 Hz), 3.71 (s, 3H), 3.68(s, 2H), 2.47 (s, 3H), 2.32 (d, 2H, J=5.0 Hz), 1.37 (t, 3H, J=7.0 Hz),1.26 (s, 6H).

6-(4-Carboxymethyl-3-fluoro-phenylethynyl)-4,4,7-trimethyl-3,4-dihydro-naphthalene-1-carboxylicacid ethyl ester Compound 56

A solution of6-(4-carboxymethyl-3-fluoro-phenylethynyl)-4,4,7-trimethyl-3,4-dihydro-naphthalene-1-carboxylicacid ethyl ester (Intermediate 187, 0.24 g, 0.54 mmol) in ethanol (2 mL)was treated with a 2M solution of lithium hydroxide (1 mL, 2 mmol) andthe resulting reaction mixture was stirred at ambient temperature for 3h. The volatiles were evaporated in vacuo, the residue was neutralizedwith saturated aqueous ammonium chloride solution and extracted withdiethyl ether and ethyl acetate. The organic phase was dried overanhydrous magnesium sulfate, filtered and evaporated in vacuo to aresidue that was purified by preparative reverse phase HPLC using 10%water in acetonitrile as the mobile phase to afford the title product(0.05 g, 22%).

¹H NMR (300 MHz, CDCl₃): δ7.69 (s, 1H), 7.41 (s, 1H), 7.27-7.19 (m, 3H),7.05 (t, 2H, J=4.7 Hz), 4.32 (q, 2H, 0.1=7.0 Hz), 3.64 (br s, 2H), 2.45(s, 3H), 2.31 (d, 2H, J=4.7 Hz), 1.37 (t, 3H, J=7.0 Hz), 1.25 (s, 6H).

6-(tert-Butyl-dimethyl-silanyloxy)-4,4,7-trimethyl-3,4-dihydro-2H-naphthalen-1-oneIntermediate 188

A solution of 6-hydroxy-4,4,7-trimethyl-3,4-dihydro-2H-naphthalen-1-one(Intermediate 171, 2.04 g, 10 mmol) in anhydrous N,N-dimethyl formamide(10 mL) under argon was treated with imidazole (1 g, 14.7 mmol) followedby tert-butyldimethylsilyl chloride (1.5 g, 10 mmol). After stirring thereaction mixture at ambient temperature overnight, it was poured intowater and extracted with diethyl ether (×2). The combined organic phasewas dried over anhydrous sodium sulfate, filtered and evaporated to aresidue that was purified by flash column chromatography on silica gel(230-400 mesh) using 8-14% ethyl acetate in hexane as the eluent toafford the title compound (2.5 g, 79%).

¹H NMR (300 MHz, CDCl₃): δ 7.74 (s, 1H), 6.65 (s, 1H), 2.56 (t, 2H,J=6.8 Hz), 2.09 (s, 3H), 1.88 (t, 2H, J=6.8 Hz), 1.24 (s, 6H), 0.93 (s,9H), 0.17 (s, 6H).

Trifluoro-methanesulfonic acid6-(tert-butyl-dimethyl-silanyloxy)-4,4,7-trimethyl-3,4-dihydro-naphthalen-1-ylester Intermediate 189

A stirred, cooled (−78° C.) solution of trifluoro-methanesulfonic acid6-(tert-butyl-dimethyl-silanyloxy)-4,4,7-trimethyl-3,4-dihydro-naphthalen-1-ylester (Intermediate 188, 2.53 g, 8 mmol) in anhydrous tetrahydrofuran(25 mL) under argon was treated with a 1M solution of sodiumbis(trimethylsilyl)amide in tetrahydrofuran (12 mL, 12 mmol). After 1 h,N-phenyltrifluoromethanesulfonimide (4.28 g, 12 mmol) was added and thereaction mixture was stirred at ambient temperature for 1 h. Thereaction was quenched with saturated aqueous ammonium chloride solution,diluted with water and extracted with diethyl ether (×2). The combinedorganic extract was dried over anhydrous magnesium sulfate, filtered andevaporated in vacuo to a residue that was subjected to flash columnchromatography on silica gel using 4% ethyl acetate in hexane as theeluent to afford the title compound (1.4 g, 39%).

¹H NMR (300 MHz, CDCl₃): δ6.90 (s, 1H), 6.49 (s, 1H), 5.53 (t, 2H, J=5.0Hz), 2.09 (d, 2H, J=5.0 Hz), 1.95 (s, 3H), 1.01 (s, 6H), 0.78 (s, 9H),0.00 (s, 6H).

6-(tert-Butyl-dimethyl-silanyloxy)-4,4,7-trimethyl-3,4-dihydro-naphthalene-1-carboxylicacid ethyl ester Intermediate 190

Following General Procedure E and using trifluoro-methanesulfonic acid6-(tert-butyl-dimethyl-silanyloxy)-4,4,7-trimethyl-3,4-dihydro-naphthalen-1-ylester (Intermediate 189, 3.4 g, 7.55 mmol), palladium acetate (0.36 g,1.62 mmol), 1,3-bis(diphenylphosphino)propane (0.36 g, 0.86 mmol),N,N-dimethylformamide (7 mL), ethanol (7 mL) and triethyl amine (7 mL)followed by flash column chromatography over silica gel (230-400 mesh)using 7% ethyl acetate in hexane as the eluent the title compound wasobtained (1.35 g, 48%).

¹H NMR (300 MHz, CDCl₃): δ 7.40 (s, 1H), 6.65 (t, 2H, J=5.0 Hz), 6.65(s, 1H), 4.08 (q, 2H, J=7.0 Hz), 2.04 (d, 2H, J=5.0 Hz), 1.96 (s, 3H),1.13 (t, 3H, J=7.0 Hz), 0.99 (s, 6H), 0.79 (s, 9H), 0.00 (s, 6H).

6-(tert-Butyl-dimethyl-silanyloxy)-4,4,7-trimethyl-1,2,3,4-tetrahydro-napthalene-1-carboxylicacid ethyl ester Intermediate 191

A solution of6-(tert-butyl-dimethyl-silanyloxy)-4,4,7-trimethyl-3,4-dihydronaphthalene-1-carboxylicacid ethyl ester (Intermediate 190, 0.95 g, 2.54 mmol) in ethanol wastreated with a slurry of 5% palladium on carbon (0.3 g) in ethyl acetate(0.5 mL) and the resulting reaction mixture was stirred under anatmosphere of hydrogen overnight. The solids were filtered over a bed ofcelite and the filtrate was evaporated in vacuo to afford the titlecompound as a viscous oil (0.95 g, ˜100%).

¹H NMR (300 MHz, CDCl₃): δ 6.66 (s, 1H), 6.51 (s, 1H), 3.95 (q, 2H,J=7.0 Hz), 3.46 (m, 1H), 1.92 (s, 3H), 1.93-1.75 (m, 2H), 1.64-1.55 (m,1H), 1.38-1.30 (m, 1H), 1.06 (s, 3H), 1.01 (t, 3H, J=7.0 Hz), 1.01 (s,3H), 0.80 (s, 9H), 0.00 (s, 6H).

4,4,7-Trimethyl-6-trifluoromethanesulfonyloxy-1,2,34-tetrahydro-naphthalene-1-carboxylicacid ethyl ester Intermediate 192

6-(Tert-butyl-dimethyl-silanyloxy)-4,4,7-trimethyl-1,2,3,4-tetrahydronaphthalene-1-carboxylicacid ethyl ester (Intermediate 191, 0.95 g, 2.54 mmol) was treated witha 1M solution of tetra-n-butyl ammonium fluoride in tetrahydrofuran (4mL, 2 mmol) under argon and the resulting reaction mixture was stirredat ambient temperature for 45 min. Water was added and the reactionmixture was extracted with 10% ethyl acetate in diethyl ether. Theorganic phase was washed with water and brine, dried over anhydroussodium sulfate, filtered and evaporated to an oil that was used for thenext step. The oil was dissolved in anhydrous dichloromethane underargon and treated with 4-(dimethylamino)pyridine (0.62 g, 5.1 mmol) andN-phenyltrifluoromethanesulfonimide (0.91 g, 2.54 mmol). After 1 h atambient temperature, the reaction mixture was subjected to flash columnchromatography using 8% ethyl acetate in hexane as the eluent to affordthe title compound as an oil (0.86 g, 86%).

¹H NMR (300 MHz, CDCl₃): δ 7.19 (s, 1H), 7.07 (s, 1H), 4.17 (q, 2H,J=7.0 Hz), 3.73 (t, 1H, J=5.9 Hz), 2.30 (s, 3H), 2.18-1.97 (m, 2H),1.87-1.78 (m, 1H), 1.70-1.56 (m, 1H), 1.31-1.25 (2s, 3H and 1t, 3H,overlapping).

4,4,7-Trimethyl-6-trimethylsilanylethynyl-1,2,3,4-tetrahydro-naphthalene-1-carboxylicacid ethyl ester Intermediate 193

Following General Procedure D in a sealed tube and using4,4,7-trimethyl-6-trifluoromethanesulfonyloxy-1,2,3,4-tetrahydro-naphthalene-1-carboxylicacid ethyl ester (Intermediate 192, 0.86 g, 2.2 mmol), triethyl amine (2mL), copper(I)iodide (0.083 g, 0.44 mmol), trimethylsilyl acetylene (2mL, 14 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.306 g,0.44 mmol) followed by flash column chromatography over silica gel(230-400 mesh) using 5% ethyl acetate in hexane as the eluent, andpreparative normal phase HPLC using 5% ethyl acetate in hexane as themobile phase in order to separate recovered starting material from theproduct, the title compound (0.26 g) was obtained.

¹H NMR (300 MHz, CDCl₃): δ 7.21 (s, 1H), 6.72 (s, 1H), 3.95 (q, 2H,J=7.0 Hz), 3.49 (t, 1H, J=5.8 Hz), 2.13 (s, 3H), 1.95-1.62 (m, 2H),1.60-1.48 (m, 1H), 1.42-1.31 (m, 1H), 1.10-1.00 (2s, 3H and 1t, 3H,overlapping), 0.04 (s, 9H).

6-(4-tert-Butoxycarbonylmethyl-phenylethynyl)-4,4,7-trimethyl-1,2,3,4-tetrahydronaphthalene-1-carboxylicacid ethyl ester Intermediate 194

4,4,7-Trimethyl-6-trimethylsilanylethynyl-1,2,3,4-tetrahydro-naphthalene-1-carboxylicacid ethyl ester (Intermediate 193, 0.26 g, 0.76 mmol) was treated witha 1M solution of tetra-n-butyl ammonium fluoride in tetrahydrofuran (3mL, 3 mmol) under argon and the resulting reaction mixture was stirredat ambient temperature for 1 h. Water was added and the reaction mixturewas extracted with diethyl ether. The organic phase was washed withwater and brine, dried over anhydrous sodium sulfate, filtered andevaporated to an oil that was used as such for the next step. FollowingGeneral Procedure B and using the oil (0.76 mmol), 4-iodo-tert-butylphenyl acetate (Reagent 10, 0.23 g, 0.72 mmol), triethyl amine (2 mL),copper(I)iodide (0.06 g, 0.32 mmol) anddichlorobis(triphenylphosphine)-palladium(II) (0.14 g, 0.2 mmol)followed by flash column chromatography over silica gel (230-400 mesh)using 12% ethyl acetate in hexane as the eluent, the title compound wasobtained as a viscous, pale yellow oil (0.23 g, 66%).

¹H NMR (300 MHz, CDCl₃): δ 7.50 (s, 1H), 7.48 (d, 2H, J=8.5 Hz), 7.24(d, 2H, J=8.5 Hz), 6.98 (s, 1H), 4.17 (q, 2H, J=7.0 Hz), 3.74 (t, 1H,J=5.8 Hz), 3.52 (s, 2H), 2.42 (s, 3H), 2.27-1.99 (m, 2H), 1.87-1.78 (m,1H), 1.63-1.44 (m, 1H), 1.43 (s, 9H), 1.32 (s, 3H), 1.26 (s, 3H), 1.23(t, 3H, buried).

6-(4-Carboxymethyl-phenylethynyl)-4,4,7-trimethyl-1,2,3,4-tetrahydro-naphthalene-1-carboxylicacid ethyl ester Compound 57

A solution of6-(4-tert-butoxycarbonylmethyl-phenylethynyl)-4,4,7-trimethyl-1,2,3,4-tetrahydro-naphthalene-1-carboxylicacid ethyl ester (Intermediate 194, 0.23 g, 0.5 mmol) in 1,4-dioxane (1mL) was treated with formic acid (3 mL) and the resulting reactionmixture was stirred at ambient temperature for 6 h. Water was added andthe reaction mixture was extracted with ethyl acetate (×2). The combinedorganic phase was washed with water, dried over anhydrous magnesiumsulfate, filtered and evaporated to an oil. Preparative reverse phaseHPLC using 10% water in acetonitrile as the mobile phase afforded thetitle compound (0.15 g, 74%). ¹H NMR (300 MHz, CDCl₃): δ 7.48 (s, 1H),7.46 (br d, 2H), 7.23 (br d, 2H), 6.96 (s, 1H), 4.17 (q, 2H, J=7.0 Hz),3.73 (t, 1H, J=5.8 Hz), 3.54 (br s, 2H), 2.40 (s, 3H), 2.29-1.95 (m,2H), 1.85-1.77 (m, 1H), 1.62-1.44 (m, 1H), 1.31 (s, 3H), 1.26 (s, 3H),1.25 (t, 3H, buried).

6-Hydroxy-2,4,4-trimethyl-3,4-dihydro-2H-naphthalen-1-one Intermediate195

A solution 6-methoxy-2,4,4-trimethyl-3,4-dihydro-2H-naphthalen-1-one(described in Journal of Pharmaceutical Sciences, 1970, 59(6), p869-870, Floyd et al. incorporated herein by reference; 1.2 g, 5.5 mmol)and sodium cyanide (2 g, 41 mmol) in anhydrous dimethylsulfoxide (15 mL)was heated at 230° C. for 24 h under argon. The reaction mixture wasthen cooled to ambient temperature, poured into ice and acidified(Caution! Hydrogen cyanide evolution!) with dilute hydrochloric acid andextracted with ethyl acetate (×2). The combined organic extract waswashed with brine (×1), dried over anhydrous sodium sulfate, filteredand evaporated to afford the title compound, which was used as such forthe next step (1 g, 89%).

Trifluoro-methanesulfonic acid6,8,8-trimethyl-5-oxo-5,6,7,8-tetrahydro-naphthalen-2-yl esterIntermediate 196

A solution of 6-hydroxy-2,4,4-trimethyl-3,4-dihydro-2H-naphthalen-1-one(Intermediate 195, 1 g, 5 mmol) and 4-(dimethylamino)pyridine (1.22 g,10 mmol) in anhydrous dichloromethane (10 mL) was treated withN-phenyltrifluoromethanesulfonimide (1.78 g, 10 mmol), and the resultingreaction mixture was stirred at ambient temperature for 2 h. Flashcolumn chromatography of the reaction mixture over silica gel (230-400mesh) using 5% ethyl acetate in hexane as the eluent afforded the titlecompound as a white solid (1.45 g, 86%).

¹H NMR (300 MHz, CDCl₃): δ 8.06 (d, 1H, J=8.5 Hz), 7.25 (d, 1H, J=2.0Hz), 6.79 (dd, 1H, J=8.5, 2.0 Hz), 2.79 (m, 1H), 1.94 (m, 2H), 1.41 (s,3H), 1.37 (s, 3H), 1.22 (d, 3H, J=6.7 Hz).

2,4,4-Trimethyl-6-trimethylsilanylethynyl-3,4-dihydro-2H-naphthalen-1-oneIntermediate 197

Following General Procedure D and using trifluoro-methanesulfonic acid6,8,8-trimethyl-5-oxo-5,6,7,8-tetrahydro-naphthalen-2-yl ester(Intermediate 196, 1.45 g, 4.3 mmol), triethyl amine (5 mL),copper(I)iodide (0.21 g, 0.26 mmol), trimethylsilyl acetylene (3 mL, 21mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.75 g, 1.07mmol) followed by flash column chromatography over silica gel (230-400mesh) using 5% ethyl acetate in hexane as the eluent, the title compound(1.28 g, ˜100%) was obtained.

¹H NMR (300 MHz, CDCl₃): δ 7.64 (d, 1H, J=7.9 Hz), 7.22 (d, 1H, J=2.0Hz), 7.08 (dd, 1H, J=7.9, 2.0 Hz), 2.50 (m, 1H), 1.94 (d, 2H, J=8.8Hz)), 1.13 (s, 3H), 1.08 (s, 3H), 0.96 (d, 3H, J=6.8 Hz), 0.00 (s, 9H).

Trifluoro-methanesulfonic acid2,4,4-trimethyl-6-trimethylsilanylethynyl-3,4-dihydro-naphthalen-1-ylester Intermediate 198

A stirred, cooled (ice bath) solution of2,4,4-trimethyl-6-trimethylsilanylethynyl-3,4-dihydro-2H-naphthalen-1-one(Intermediate 197, 1.28 g, 4.5 mmol) in anhydrous dichloromethane (10mL) was treated with 2,6-di-t-butyl-4-methylpyridine (2.04 g, 9.91 mmol)and trifluoromethanesulfonic anhydride (1.52 mL, 9 mmol) and theresulting reaction mixture was stirred at ambient temperature for 5 daysat the end of which it was subjected to flash column chromatography onsilica gel (230-400 mesh) using 5% ethyl acetate in hexane as the eluentto afford the title compound as an oil (1.59 g, 85%).

¹H NMR (300 MHz, CDCl₃): δ 7.09 (d, 1H, J=7.9 Hz), 7.07 (d, 1H, J=1.5Hz), 6.98 (dd, 1H, J=7.9, 1.5 Hz), 2.04 (s, 2H), 1.72 (s, 3H), 1.03 (s,6H), 0.00 (s, 9H).

2,4,4-Trimethyl-6-trimethylsilanylethynyl-3,4-dihydro-naphthalene-1-carboxylicacid ethyl ester Intermediate 199

Following General Procedure E and using trifluoro-methanesulfonic acid2,4,4-trimethyl-6-trimethylsilanylethynyl-3,4-dihydro-naphthalen-1-ylester (Intermediate 198, 1.59 g, 3.8 mmol), palladium acetate (0.1 g,0.45 mmol), 1,3-bis(diphenylphosphino)propane (0.1 g, 0.24 mmol),N,N-dimethylformamide (2.4 mL), ethanol (2.4 mL) and triethyl amine (2.4mL) followed by flash column chromatography over silica gel (230-400mesh) using 5% ethyl acetate in hexane as the eluent the title compoundwas obtained (0.31 g, 24%) as a yellow oil.

¹H NMR (300 MHz, CDCl₃): δ 7.12 (d, 1H, J=1.5 Hz), 7.01 (dd, 1H, J=8.2,1.8 Hz), 6.77 (d, 1H, J=8.2 Hz), 4.10 (q, 2H, J=7.0 Hz), 1.93 (s, 2H),1.73 (s, 3H), 1.08 (t, 3H, J=7.0 Hz), 0.99 (s, 6H), 0.00 (s, 9H).

6-Ethynyl-2,4,4-trimethyl-3,4-dihydro-naphthalene-1-carboxylic acidethyl ester Intermediate 200

Following general procedure F and using2,4,4-trimethyl-6-trimethylsilanylethynyl-3,4-dihydro-naphthalene-1-carboxylicacid ethyl ester (Intermediate 199, 0.31 g, 0.92 mmol), ethanol (2 mL)and potassium carbonate (0.3 g, 2.2 mmol), the title compound wasobtained (0.26 g, >100%).

¹H NMR (300 MHz, CDCl₃): δ 7.32 (d, 1H, J=1.5 Hz), 7.20 (dd, 1H, J=8.2,1.5 Hz), 6.96 (d, 1H, J=8.2 Hz), 4.27 (q, 2H, J=7.0 Hz), 3.00 (s, 1H),2.10 (s, 2H), 1.90 (s, 3H), 1.27 (t, 3H, J=7.0 Hz), 1.16 (s, 6H).

6-(4-Methoxycarbonylmethyl-phenylethynyl)-2,4,4-trimethyl-3,4-dihydro-naphthalene-1-carboxylicacid ethyl ester Intermediate 201

Following General Procedure B and using6-ethynyl-2,4,4-trimethyl-3,4-dihydro-naphthalene-1-carboxylic acidethyl ester (Intermediate 200, 0.106 g, 0.38 mmol), 4-iodo phenyl aceticacid methyl ester (0.106 g, 0.38 mmol), triethyl amine (2 mL),copper(I)iodide (0.02 g, 0.105 mmol) anddichlorobis(triphenylphosphine)palladium(II) (0.07 g, 0.1 mmol) followedby flash column chromatography over silica gel (230-400 mesh) using12-15% ethyl acetate in hexane as the eluent, the title compound wasobtained as a pale yellow oil (0.075 g, 47%).

¹H NMR (300 MHz, CDCl₃): δ 7.49 (d, 2H, J=7.9 Hz), 7.45 (d, 1H, J=1.5Hz), 7.32 (dd, 1H, J=7.9, 1.5 Hz), 7.26 (d, 2H, J=7.9 Hz), 7.07 (d, 1H,J=7.9 Hz), 4.37 (q, 2H, J=7.0 Hz), 3.70 (s, 3H), 3.63 (s, 2H), 2.22 (s,2H), 2.00 (s, 3H), 1.38 (t, 3H, J=7.0 Hz), 1.27 (s, 6H).

6-(4-Carboxymethyl-phenylethynyl)-2,4,4-trimethyl-3,4-dihydro-naphthalene-1-carboxylicacid ethyl ester Compound 58

A solution of6-(4-carboxymethyl-phenylethynyl)-2,4,4-trimethyl-3,4-dihydronaphthalene-1-carboxylicacid ethyl ester (0.075 g, 0.18 mmol) in ethanol (2 mL) was treated witha 1M solution of lithium hydroxide (1 mL, 1 mmol) and the resultingreaction mixture was stirred at ambient temperature for 0.5 h. Thevolatiles were evaporated in vacuo, the residue was neutralized withsaturated aqueous ammonium chloride solution and extracted with diethylether and ethyl acetate. The organic phase was dried over anhydrousmagnesium sulfate, filtered and evaporated in vacuo to afford the titleproduct (0.055 g, 76%).

¹H NMR (300 MHz, CDCl₃): δ 7.48 (d, 2H, J=7.9 Hz), 7.44 (d, 1H, J=1.5Hz), 7.31 (dd, 1H, J=7.9, 1.7 Hz), 7.23 (br d, 2H, J=7.7 Hz), 7.06 (d,1H, J=7.9 Hz), 4.36 (q, 2H, J=7.0 Hz), 3.60 (br s, 2H), 2.20 (s, 2H),1.99 (s, 3H), 1.37 (t, 3H, J=7.0 Hz), 1.26 (s, 6H).

6-(3-Fluoro-4-methoxycarbonylmethyl-phenylethynyl)-2,4,4-trimethyl-3,4-dihydronaphthalene-1-carboxylicacid ethyl ester Intermediate 202

Following General Procedure B and using6-ethynyl-2,4,4-trimethyl-3,4-dihydro-naphthalene-1-carboxylic acidethyl ester (0.16 g, 0.59 mmol), 2-fluoro-4-iodo phenyl acetic acidmethyl ester (Intermediate 200, 0.16 g, 0.56 mmol), triethyl amine (2mL), copper(I)iodide (0.07 g, 0.37 mmol) anddichlorobis(triphenylphosphine)palladium(II) (0.11 g, 0.16 mmol)followed by flash column chromatography over silica gel (230-400 mesh)using 12-15% ethyl acetate in hexane as the eluent, the title compoundwas obtained as a viscous oil (0.15 g, 58%).

¹H NMR (300 MHz, CDCl₃): δ 7.44 (d, 1H, J=1.5 Hz), 7.32 (dd, 1H, J=7.9,1.5 Hz), 7.30-7.19 (m, 3H), 7.08 (d, 1H, J=7.9 Hz), 4.37 (q, 2H, J=7.0Hz), 3.71 (s, 3H), 3.68 (s, 2H), 2.21 (s, 2H), 2.00 (s, 3H), 1.37 (t,3H, J=7.0 Hz), 1.27 (s, 6H).

6-(4-Carboxymethyl-3-fluoro-phenylethynyl)-2,4,4-trimethyl-3,4-dihydro-naphthalene-1-carboxylicacid ethyl ester Compound 59

A solution of6-(4-carboxymethyl-3-fluoro-phenylethynyl)-2,4,4-trimethyl-3,4-dihydro-naphthalene-1-carboxylicacid ethyl ester (Intermediate 202, 0.15 g, 0.35 mmol) in ethanol (2 mL)was treated with a 1M solution of lithium hydroxide (1 mL, 1 mmol) andthe resulting reaction mixture was stirred at ambient temperature for0.5 h. The volatiles were evaporated in vacuo, the residue wasneutralized with saturated aqueous ammonium chloride solution andextracted with diethyl ether and ethyl acetate. The organic phase wasdried over anhydrous magnesium sulfate, filtered and evaporated in vacuoto afford the title product (0.1 g, 67%).

¹H NMR (300 MHz, CDCl₃): δ 7.44 (d, 1H, J=1.5 Hz), 7.32 (dd, 1H, J=8.2,1.5 Hz), 7.22-7.18 (m, 3H), 7.07 (d, 1H, J=7.9 Hz), 4.36 (q, 2H, J=7.0Hz), 3.66 (br s, 2H), 2.20 (s, 2H), 1.99 (s, 3H), 1.37 (t, 3H, J=7.0Hz), 1.26 (s, 6H).

[4-(8,8-Dimethyl-5-trifluoromethanesulfonyloxy-7,8-dihydro-naphthalen-2-ylethynyl)-2-fluoro-phenyl]-aceticacid methyl ester Intermediate 203

A solution of[4-(8,8-dimethyl-5-oxo-5,6,7,8-tetrahydro-naphthalen-2-ylethynyl)-2-fluoro-phenyl]-aceticacid methyl ester (U.S. Pat. No. 6,252,090; 0.28 g, 0.77 mmol) inanhydrous dichloromethane (5 mL) was treated with2,6-di-1-butyl-4-methylpyridine (0.189 g, 0.92 mmol) andtrifluoromethanesulfonic anhydride (0.136 mL, 0.81 mmol) and theresulting reaction mixture was stirred at ambient temperature for 4 h atthe end of which it was diluted with water and extracted with ethylacetate. The organic extract was washed with water and brine, dried overanhydrous sodium sulfate, filtered and evaporated in vacuo to a residuethat was subjected to flash column chromatography on silica gel (230-400mesh) using 5% ethyl acetate in hexane as the eluent to afford the titlecompound as a pale orange oil (0.32 g, 84%).

¹H NMR (300 MHz, CDCl₃): δ 7.46-7.22 (m, 6H), 6.00 (t, J=4.8 Hz, 1H),3.72 (s, 3H), 3.70 (s, 2H), 2.41 (d, J=4.8 Hz, 2H), 1.33 (s, 6H).

6-(3-Fluoro-4-methoxycarbonylmethyl-phenylethynyl)-4,4-dimethyl-3,4-dihydronaphthalene-1-carboxylicacid ethyl ester Intermediate 204

Following General Procedure E and using[4-(8,8-dimethyl-5-trifluoromethanesulfonyloxy-7,8-dihydro-naphthalen-2-ylethynyl)-2-fluoro-phenyl]-aceticacid methyl ester (Intermediate 203, 0.32 g, 0.65 mmol), palladiumacetate (0.015 g, 0.064 mmol), 1,3-bis(diphenylphosphino)propane (0.027g, 0.064 mmol), N,N-dimethylformamide (5 mL), ethanol (2 mL) andtriethyl amine (2 mL) followed by flash column chromatography oversilica gel (230-400 mesh) using 5-15% ethyl acetate in hexane as theeluent the title compound was obtained (0.15 g, 55%) as a yellow oil.

¹H NMR (300 MHz, CDCl₃): δ 7.84 (d, J=8.2 Hz, 1H), 7.47 (d, J=1.7 Hz,1H), 7.37 (dd, J=8.2, 1.7 Hz, 1H), 7.30-7.15 (m, 3H), 7.08 (t, J=4.8 Hz,1H), 4.31 (q, J=7.0 Hz, 2H), 3.71 (s, 3H), 3.68 (s, 2H), 2.34 (d, J=4.8Hz, 2H), 1.37 (t, J=7.0 Hz, 3H), 1.28 (s, 6H).

6-(4-Carboxymethyl-3-fluoro-phenylethynyl)-4,4-dimethyl-3,4-dihydro-naphthalene-1-carboxylicacid ethyl ester Compound 60

A solution of6-(3-fluoro-4-methoxycarbonylmethyl-phenylethynyl)-4,4-dimethyl-3,4-dihydro-naphthalene-1-carboxylicacid ethyl ester (Intermediate 204, 0.15 g, 0.36 mmol) in ethanol (3 mL)and tetrahydrofuran (3 mL) was treated with a 2M solution of lithiumhydroxide (1.5 mL, 3 mmol) and the resulting reaction mixture wasstirred at ambient temperature for 1.5 h. The volatiles were evaporatedin vacuo, the residue was neutralized with saturated aqueous ammoniumchloride solution and extracted with diethyl ether and ethyl acetate.The organic phase was dried over anhydrous magnesium sulfate, filteredand evaporated in vacuo to a residue that was purified by preparativereverse phase HPLC using 5% water in acetonitrile as the mobile phase toafford the title product (0.04 g, 27%). ¹H NMR (300 MHz, CDCl₃): δ 7.81(d, J=8.2 Hz, 1H), 7.46 (d, J=1.7 Hz, 1H), 7.37 (dd, J=8.2 &1.7 Hz, 1H),7.27-7.09 (m, 3H), 7.07 (t, J=4.8 Hz, 1H), 4.31 (q, J=7.0 Hz, 2H), 3.66(s, 2H), 2.33 (d, J=4.8 Hz, 2H), 1.37 (t, J=7.0 Hz, 3H), 1.27 (s, 6H).

3,5-Dibromo-benzoic acid isopropyl ester Intermediate 205

A solution of 3,5-dibromobenzoic acid (Aldrich, 2.4 g, 8.6 mmol) inbenzene (150 mL) and isopropanol (50 mL) was treated with concentratedsulfuric acid (2 mL) and heated to reflux overnight using a Dean-Starkwater trap. The volatiles were evaporated in vacuo, the residue wasdiluted with water and extracted with diethyl ether. The organic phasewas washed with water and saturated, aqueous sodium bicarbonatesolution, dried over anhydrous magnesium sulfate, filtered andevaporated in vacuo to afford the title product as a clear oil that wasused as such for the next step (2.7 g, ˜100%).

3,5-Diethynyl-benzoic acid isopropyl ester Intermediate 206

Following General Procedure D and using 3,5-dibromo-benzoic acidisopropyl ester (Intermediate 205, 2.7 g, 8.6 mmol), triethyl amine (30mL), copper(I)iodide (0.45 g, 2.4 mmol), trimethylsilyl acetylene (6.8mL, 48 mmol) and dichlorobis(triphenylphosphine)palladium(II) (1.75 g,2.4 mmol) followed by flash column chromatography over silica gel(230-400 mesh) using 3% ethyl acetate in hexane as the eluent, theintermediate 3,5-bis-trimethylsilanylethynyl-benzoic acid isopropylester was obtained. The intermediate (2.8 g, 7.85 mmol) was treated witha 1M solution of tetra-n-butyl ammonium fluoride in tetrahydrofuran (25mL, 25 mmol) and the resulting reaction mixture was stirred in an icebath for 1 h. Water was added and the reaction mixture was extractedwith diethyl ether. The organic phase was washed with water and brine,dried over anhydrous sodium sulfate, filtered and evaporated to an oilthat was redissolved in diethyl ether (10 mL) and treated with hexane(150 mL). The solid that precipitated out was filtered and dried toafford the title compound (1.3 g, 78%).

¹H NMR (300 MHz, CDCl₃): δ 8.08 (d, 1H, J=1.4 Hz), 7.73 (d, 1H, J=1.4Hz), 5.23 (heptet, 1H, J=6.3 Hz), 3.13 (s, 2H), 1.35 (d, 6H, J=6.1 Hz).

3-Ethynyl-5-[3-fluoro-4-(3-trimethylsilanyl-propoxycarbonylmethyl)-phenylethynyl]-benzoicacid isopropyl ester Intermediate 207

Following General Procedure B and using 3,5-diethynyl-benzoic acidisopropyl ester (Intermediate 206, 0.36 g, 1.72 mmol),(2-fluoro-4-iodo-phenyl)-acetic acid 2-trimethylsilanyl-ethyl ester(0.132 g, 0.86 mmol), triethyl amine (8 mL), copper(I)iodide (0.019 g,0.1 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.07 g, 0.1mmol) followed by flash column chromatography over silica gel (230-400mesh) using 5-10% ethyl acetate in hexane as the eluent, the titlecompound was obtained as a colorless oil (0.15 g, 37%).

¹H NMR (300 MHz, CDCl₃): δ 8.10 (m, 1H), 8.07 (m, 1H), 7.75 (m, 1H),7.19-7.25 (m, 3H), 5.24 (hept, J=6.2 Hz, 1H), 4.19 (t, J=8.5 Hz, 2H),3.64 (s, 2H), 3.14 (s, 1H), 1.35 (d, J=6.2 Hz, 6H), 0.97 (t, J=8.5 Hz,2H), 0.00 (s, 9H).

3-(4-Carboxymethyl-3-fluoro-phenylethynyl)-5-ethynyl-benzoic acidisopropyl ester Compound 61

A solution of3-ethynyl-5-[3-fluoro-4-(3-trimethylsilanyl-propoxycarbonylmethyl)-phenylethynyl]-benzoicacid isopropyl ester (Intermediate 207, 0.15 g, 0.32 mmol) in anhydrousdimethysulfoxide (4 mL) was treated with tetra-n-ethyl ammonium fluoride(0.19 mL, 1.3 mmol) and the resulting reaction mixture was stirred atambient temperature for 5 min. Water was added and the reaction mixturewas extracted with ethyl acetate. The organic phase was washed withwater and brine, dried over anhydrous sodium sulfate, filtered andevaporated to an oil that was purified by recrystallization from ethylacetate/hexane to afford the title compound as a white solid (0.045 g,38%).

¹H NMR (300 MHz, CDCl₃): δ 8.13 (m, 1H), 8.10 (m, 1H), 7.78 (m, 1H),7.23-7.30 (m, 3H), 5.29 (hept, J=6.4 Hz, 1H), 3.74 (s, 2H), 3.15 (s,1H), 1.38 (d, J=6.4 Hz, 6H).

3-(4-Acetoxymethoxycarbonylmethyl-3-fluoro-phenylethynyl)-5-ethynyl-benzoicacid isopropyl ester Compound 62

Following General Procedure B and using 3,5-diethynyl-benzoic acidisopropyl ester (Intermediate 206, 0.27 g, 1.27 mmol),(2-fluoro-4-iodo-phenyl)-acetic acid acetoxymethyl ester (0.224 g, 0.64mmol), triethyl amine (8 mL), copper(I)iodide (0.019 g, 0.1 mmol) anddichlorobis(triphenylphosphine)palladium(II) (0.07 g, 0.1 mmol) followedby flash column chromatography over silica gel (230-400 mesh) using2.5-20% ethyl acetate in hexane as the eluent, the title compound wasobtained as an orange solid (0.09 g, 32%).

¹H NMR (300 MHz, CDCl₃): δ 8.13 (m, 1H), 8.10 (m, 1H), 7.79 (m, 1H),7.23-7.32 (m, 3H), 5.78 (s, 2H), 5.27 (hept, J=6.4 Hz, 1H), 3.75 (s,2H), 3.15 (s, 1H), 2.12 (s, 3H), 1.38 (d, J=6.4 Hz, 6H).

Ethyl-8-iodo-2,2,4,4-tetramethyl chroman-6-carboxylate Intermediate 208

A solution of ethyl-2,2,4,4-tetramethyl chroman-6-carboxylate(Intermediate 36, 0.733 g, 2.8 mmol) in anhydrous dichloromethane (10mL) was treated with silver(I)trifluoromethanesulfonate (0.719 g, 2.8mmol) and iodine (0.71 g, 2.8 mmol) and the resulting solution wasstirred at ambient temperature for 4 h. The reaction mixture was treatedwith saturated, aqueous sodium thiosulfate solution and extracted withethyl acetate. The organic phase was dried over anhydrous magnesiumsulfate, filtered and evaporated in vacuo to a residue which wassubjected to flash column chromatography over silica gel (230-400 mesh)using 5-10% ethyl acetate in hexane as the eluent to afford the titlecompound (0.88 g, 81%) as a pale yellow oil.

¹H NMR (300 MHz, CDCl₃): δ 8.26 (d, 1H, J=2.0 Hz), 7.96 (d, 1H, J=2.0Hz), 4.34 (q, 2H, J=7.1 Hz), 1.87 (s, 2H), 1.40 (s, 6H), 1.37 (s, 6H),1.41-1.35 (m, 3H).

Ethyl-8-trimethylsilanylethynyl-2,2,4,4-tetramethylchroman-6-carboxylate Intermediate 209

A solution of ethyl-8-iodo-2,2,4,4-tetramethyl chroman-6-carboxylate(Intermediate 208, 0.88 g, 2.26 mmol) in triethyl amine (10 mL) wastreated with copper(I)iodide (0.043 g, 0.226 mmol) and sparged withargon for 5 minutes. Trimethylsilyl acetylene (3 mL, 21.22 mmol) wasthen added followed by dichlorobis(triphenylphosphine)palladium(II)(0.159 g, 0.226 mmol). The resulting reaction mixture was heated at 70°C. overnight in a sealed tube. It was then cooled to ambienttemperature, diluted with diethyl ether and filtered over a bed ofcelite. The filtrate was evaporated vacuo to an oil which was subjectedto flash column chromatography over silica gel (230-400 mesh) using 10%ethyl acetate in hexane as the eluent to afford the title compound(0.803 g, 99%).

¹H NMR (300 MHz, CDCl₃): δ 7.93 (s, 1H), 7.92 (s, 1H), 4.32 (q, 2H,J=7.0 Hz), 1.86 (s, 2H), 1.38 (s, 6H), 1.34 (s, 6H), 1.38-1.34 (m, 3H),0.24 (s, 9H).

8-Ethynyl-2,2,4,4-tetramethyl chroman-6-carboxylic acid Intermediate 210

A solution ofethyl-8-trimethylsilanylethynyl-2,2,4,4-tetramethylchroman-6-carboxylate(Intermediate 209, 0.525 g, 1.47 mmol) in ethanol (5 mL) was treatedwith 2N aqueous sodium hydroxide solution (5 mL, 10 mmol) and theresulting solution was adjusted to pH ˜15 with 10% aqueous hydrochloricacid and extracted with ethyl acetate. The organic phase was dried overanhydrous magnesium sulfate, filtered and evaporated in vacuo to affordthe title product as a brown solid (0.316 g, 84%).

¹H NMR (300 MHz, CDCl₃): δ 8.02 (s, 2H), 3.23 (s, 1H), 1.89 (s, 2H),1.42 (s, 6H), 1.38 (s, 6H).

8-Ethynyl-2,2,4,4-tetramethyl-chroman-6-carboxylic acid azideIntermediate 211

A stirred, cooled (ice bath) solution of8-ethynyl-2,2,4,4-tetramethyl-chroman-6-carboxylic acid (Intermediate210, 0.52 g, 2 mmol) in anhydrous tetrahydrofuran (10 mL) under argon,was treated with triethyl amine (0.86 mL, 6 mmol) followed by ethylchloroformate (0.25 mL, 2.6 mmol) and the resulting reaction mixture wasallowed to warm to ambient temperature and stirred for 2 h. Sodium azide0.19 g, 3 mmol) was added and the reaction mixture was stirredovernight. The reaction mixture was then diluted with water andextracted with diethyl ether. The organic extract was dried overanhydrous magnesium sulfate, filtered and evaporated to a residue thatwas purified by flash column chromatography over silica gel (230-400mesh) to afford the title compound as a yellow solid (0.32 g, 56%).

¹H NMR (300 MHz, CDCl₃): δ 7.96 (ABq, 2H, J=2.1 Hz), 3.24 (s, 1H), 1.89(s, 2H), 1.42 (s, 6H), 1.37 (s, 6H).

4-[3-(8-Ethynyl-2,2,4,4-tetramethyl-chroman-6-yl)-ureido]-2-fluoro-benzoicacid ethyl ester Intermediate 212

A solution of 8-ethynyl-2,2,4,4-tetramethyl-chroman-6-carboxylic acidazide (Intermediate 211, 0.104 g, 0.37 mmol) in anhydrous toluene wasrefluxed under argon overnight. Ethyl-4-amino-2-fluoro-benzoate(described in Teng et al, Journal of Medicinal Chemistry, 1996, 39, p3035-3038, 0.114 g, 0.622 mmol) was added and the reaction mixture wasrefluxed for 5.5 h. The reaction mixture was cooled to ambienttemperature and subjected to flash column chromatography over silica gel(230-400 mesh) using 20-33% ethyl acetate in hexane as the eluent toafford the title compound contaminated with someethyl-4-amino-2-fluoro-benzoate. It was used as such for the next step.

4-[3-(8-Ethynyl-2,2,4,4-tetramethyl-chroman-6-yl)-ureido]-2-fluoro-benzoicacid Compound 63

A solution of4-[3-(8-ethynyl-2,2,4,4-tetramethyl-chroman-6-yl)-ureido]-2-fluoro-benzoicacid ethyl ester (Intermediate 212, 0.12 g) in methanol (2 mL),tetrahydrofuran (2 mL) and water (1 mL) was treated with lithiumhydroxide (0.177 g, 4.2 mmol) and the resulting reaction mixture wasstirred at ambient temperature overnight. The volatiles were evaporatedin vacuo, the residue was diluted with water and neutralized with dilutehydrochloric acid and extracted with ethyl acetate. The organic phasewas dried over anhydrous magnesium sulfate, filtered and evaporated toafford the title compound as a solid (0.07 g, 46% for two steps).

¹H NMR (300 MHz, CD₃OD): δ 7.86 (dd, 1H, J=8.8, 8.5 Hz), 7.53 (dd, 1H,J=13.7, 2.0 Hz), 7.42 (d, 1H, J=2.3 Hz), 7.28 (d, 1H, J=2.3 Hz), 7.14(dd, 1H, J=2.0, 8.8 Hz), 3.50 (s, 1H), 1.86 (s, 2H), 1.35 (s, 12H).

1. A compound of the formula

Wherein A is a phenyl or naphthyl group, or heteroaryl selected from agroup consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl,pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyland heteroaryl groups being optionally substituted with one or two R₂groups; X is O, S or NR where R is H, alkyl of 1 to 6 carbons or benzyl;Y is H, alkyl of 1 to 10 carbons, benzyl, C₁₋₆ alkyl or halogensubstituted benzyl, fluoro-substituted alkyl of 1 to 10 carbons,cycloalkyl of 3 to 6 carbons, C₁₋₆ alkyl or substituted cycloalkyl of 3to 6 carbons, alkenyl of 2 to 6 carbons and having 1 or 2 double bonds,alkynyl of 2 to 6 carbons, alkenyl-alkynyl of 4 to 6 carbons,alkynyl-alkenyl of 4 to 6 carbons, Cl, Br, or I or alkoxy of 1 to 6carbons; Z is —C≡C—, —(CR₁═CR₁)_(n′) where n′ is an integer having thevalue 1-5, —CO—NR₁—, NR₁—CO—; —CO—O—, —O—CO—, —CS—NR₁— NR₁—CS—, —CO—S—,—N═N—; —NR₁—CO—NR₁—; R₁ is independently H or alkyl of 1 to 6 carbons; pis an integer having the values of 0 to 4; R₂ is independently H, alkylof 1 to 6 carbons, F, Cl, Br, I, CF₃, fluoro substituted alkyl of 1 to 6carbons, alkoxy of 1 to 6 carbons, or alkylthio of 1 to 6 carbons; R₃ isindependently alkyl of 1 to 6 carbons, F, Cl, Br, I, fluoro substitutedalkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons, alkylthio of1 to 6 carbons or benzyl; m is an integer having the values 0 to 2; R₄is independently H, alkyl of 1 to 6 carbons, or F; fluorosubstitutedalkyl of 1 to 6 carbons, or halogen; o is an integer having the valuesof 0 to 2; W is —C(R₅)₂— or —CR₅═CR₅—; R₅ is independently H, halogen,or alkyl of 1 to 3 carbons with the proviso that when W is —C(R₅)₂— thenat least one R₅ is alkyl of 1 to 3 carbons, and R₈ is H, alkyl of 1 to 6carbons, —CH₂O(C₁₋₆-alkyl), CH₂OCO(C₁₋₆-alkyl) or a cation of apharmaceutically acceptable base. 2-6. (canceled)
 7. A compound of theformula

wherein the dashed line represents a bond or absence of a bond; A is aphenyl or naphthyl group, or heteroaryl selected from a group consistingof pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl,thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyl andheteroaryl groups being optionally substituted with one or two R₂groups; X is alkyl of 1 to 6 carbons, alkenyl of 2 to 6 carbons andhaving 1 or 2 double bonds, alkynyl of 2 to 6 carbons, alkenyl-alkynylof 4 to 6 carbons, alkynyl-alkenyl of 4 to 6 carbons, Cl, Br, or I, OR,SR, NRR₇, —CO—OR where R is H, alkyl of 1 to 6 carbons or benzyl; Y isH, alkyl of 1 to 10 carbons, benzyl, C₁₋₆ alkyl or halogen substitutedbenzyl, fluoro-substituted alkyl of 1 to 10 carbons, cycloalkyl of 3 to6 carbons, C₁₋₆ alkyl substituted cycloalkyl of 3 to 6 carbons, alkenylof 2 to 6 carbons and having 1 or 2 double bonds, alkynyl of 2 to 6carbons, alkenyl-alkynyl of 4 to 6 carbons, alkynyl-alkenyl of 4 to 6carbons, Cl, Br, I, COOR₈ or alkoxy of 1 to 6 carbons; Z is —C≡C—,—(CR₁═CR₁)_(n′) where n′ is an integer having the value 1-5, —CO—NR₁—,NR₁—CO—; —CO—O—, —O—CO—, —CS—NR₁—, NR₁—CS—, —CO—S—, —N═N—; —NR₁—CO—NR₁—;R₁ is independently H or alkyl of 1 to 6 carbons; R₂ is independently H,alkyl of 1 to 6 carbons, F, Cl, Br, I, CF₃, fluoro substituted alkyl of1 to 6 carbons, alkoxy of 1 to 6 carbons, or alkylthio of 1 to 6carbons; R₃ is independently alkyl of 1 to 6 carbons, F, Cl, Br, I,fluoro substituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6carbons, alkylthio of 1 to 6 carbons or benzyl; m is an integer havingthe values 0 to 2; R₄ is independently H, alkyl of 1 to 6 carbons, orfluorosubstituted alkyl of 1 to 6 carbons, or halogen; o is an integerhaving the values of 0 to 4; W is —C(R₅)₂— or —CR₅═CR₅—; R₅ isindependently H, halogen, or alkyl of 1 to 3 carbons with the provisothat when W is —C(R₅)₂— then at least one R₅ is alkyl of 1 to 3 carbons;R₇ is H, lower alkyl, cycloalkyl of 3 to 6 carbons, lower alkylsubstituted cycloalkyl of 3 to 6 carbons, and R₈ independently is H,alkyl of 1 to 6 carbons, —CH₂O(C₁₋₆-alkyl), CH₂OCO(C₁₋₆-alkyl) or acation of a pharmaceutically acceptable base. 8-13. (canceled)
 14. Acompound of the formula

wherein A is a phenyl or naphthyl group, or heteroaryl selected from agroup consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl,pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyland heteroaryl groups being optionally substituted with one or two R₂groups; X is O, S or NR where R is H, alkyl of 1 to 6 carbons,C₁₋₆-trialkylsilyl or benzyl; Y is H, alkyl of 1 to 10 carbons, benzyl,C₁₋₆ alkyl or halogen substituted benzyl, fluoro-substituted alkyl of 1to 10 carbons, cycloalkyl of 3 to 6 carbons, C₁₋₆ alkyl substitutedcycloalkyl of 3 to 6 carbons, alkenyl of 2 to 6 carbons and having 1 or2 double bonds, alkynyl of 2 to 6 carbons, alkenyl-alkynyl of 4 to 6carbons, alkynyl-alkenyl of 4 to 6 carbons, Cl, Br, or I; Z is —C≡C—,—(CR₁═CR₁)_(n′) where n′ is an integer having the value 1-5, —CO—NR₁—,NR₁—CO—; —CO—O—, —O—CO—, —CS—NR₁—, NR₁—CS—, —CO—S—, —N═N—; —NR₁—CO—NR₁—;R₁ is independently H or alkyl of 1 to 6 carbons; R₂ is independently H,alkyl of 1 to 6 carbons, F, Cl, Br, I, CF₃, fluoro substituted alkyl of1 to 6 carbons, alkoxy of 1 to 6 carbons, or alkylthio of 1 to 6carbons; R₃ is independently alkyl of 1 to 6 carbons, F, Cl, Br, I,fluoro substituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6carbons, alkylthio of 1 to 6 carbons or benzyl; m is an integer havingthe values 0 to 3; W is —C(R₅)₂— or —CR₅═CR₅—; R₅ is independently H,halogen, or alkyl of 1 to 3 carbons with the proviso that when W is—C(R₅)₂— then at least one R₅ is alkyl of 1 to 3 carbons; R₇ is H, alkylof 1 to 6 carbons, cycloalkyl of 3 to 6 carbons or C₁₋₆ alkylsubstituted cycloalkyl of 1 to 6 carbons, and R₈ is H, alkyl of 1 to 6carbons, —CH₂O(C₁₋₆-alkyl), CH₂OCO(C₁₋₆-alkyl) or a cation of apharmaceutically acceptable base.
 15. A compound in accordance withclaim 14 where A is selected from the group consisting of phenyl,naphthyl, pyridyl, thienyl and furyl.
 16. A compound in accordance withclaim 15 where A is phenyl.
 17. A compound in accordance with claim 14where Z is selected from the group consisting of —C≡C—, —CO—O— and—NHCONH—.
 18. A compound in accordance with claim 14 where W is selectedfrom the group consisting of CH═CH, C(CH₃)═CH, CH═C(CH₃), C(CH₃)₂ andCHCH₃.
 19. A compound in accordance with claim 16 where Z is —C≡C—, Y isH, X is NR and R₈ is H, lower alkyl of 1 to 3 carbons, —CH₂O(C₁₋₃-alkyl)or —CH₂OCO(C₁₋₃-alkyl) or a cation of a pharmaceutically acceptablebase.
 20. A compound of the formula

Wherein A is a phenyl or naphthyl group, or heteroaryl selected from agroup consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl,pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyland heteroaryl groups being optionally substituted with one or two R₂groups; X is OR₇, SR₇ or NRR₇ where R is H, alkyl of 1 to 6 carbons orbenzyl; Y is H, alkyl of 1 to 10 carbons, benzyl, C₁₋₆ alkyl or halogensubstituted benzyl, fluoro-substituted alkyl of 1 to 10 carbons,cycloalkyl of 3 to 6 carbons, C₁₋₆ alkyl substituted cycloalkyl of 3 to6 carbons, alkenyl of 2 to 6 carbons and having 1 or 2 double bonds,alkynyl of 2 to 6 carbons, alkenyl-alkynyl of 4 to 6 carbons,alkynyl-alkenyl of 4 to 6 carbons, Cl, Br, I, or —COOR₁; Z is —C≡C—,—(CR₁═CR₁)_(n′) where n′ is an integer having the value 1-5, —CO—NR₁—,NR₁—CO—; —CO—O—, —O—CO—, —CS—NR₁—, NR₁—CS—, —CO—S—, —N═N—; —NR₁—CO—NR₁—;R₁ is independently H or alkyl of 1 to 6 carbons; R₂ is independently H,alkyl of 1 to 6 carbons, F, Cl, Br, I, CF₃, fluoro substituted alkyl of1 to 6 carbons, alkoxy of 1 to 6 carbons, or alkylthio of 1 to 6carbons; R₃ is independently alkyl of 1 to 6 carbons, F, Cl, Br, I,fluoro substituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6carbons, alkylthio of 1 to 6 carbons or benzyl; m is an integer havingthe values 0 to 3; W is —C(R₅)₂— or —CR₅═CR₅—; R₅ is independently H,halogen, or alkyl of 1 to 3 carbons with the proviso that when W is—C(R₅)₂— then at least one R₅ is alkyl of 1 to 3 carbons; R₇ is H, alkylof 1 to 6 carbons, cycloalkyl of 3 to 6 carbons or C₁₋₆ alkylsubstituted cycloalkyl of 1 to 6 carbons, and R₈ is H, alkyl of 1 to 6carbons, —CH₂O(C₁₋₆-alkyl), CH₂OCO(C₁₋₆-alkyl) or a cation of apharmaceutically acceptable base.
 21. A compound in accordance withclaim 20 where A is selected from the group consisting of phenyl,naphthyl, pyridyl, thienyl and furyl
 22. A compound in accordance withclaim 21 where A is phenyl.
 23. A compound in accordance with claim 20where Z is selected from the group consisting of —C≡C—, —CO—O— and—NHCONH—.
 24. A compound in accordance with claim 20 where W is selectedfrom the group consisting of CH═CH, C(CH₃)═CH, CH═C(CH₃), C(CH₃)₂ andCHCH₃.
 25. A compound in accordance with claim 22 where Z is —C≡C—, Y isH or COOR₁, X is NRR₇ where R₇ is cyclopropyl and R₈ is H, lower alkylof 1 to 3 carbons, —CH₂O(C₁₋₃-alkyl) or —CH₂OCO(C₁₋₃-alkyl) or a cationof a pharmaceutically acceptable base.
 26. (canceled)
 27. A compound ofthe formula

wherein A is a phenyl or naphthyl group, or heteroaryl selected from agroup consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl,pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyland heteroaryl groups being optionally substituted with one or two R₂groups; Y is H, alkyl of 1 to 10 carbons, benzyl, C₁₋₆ alkyl or halogensubstituted benzyl, fluoro-substituted alkyl of 1 to 10 carbons,cycloalkyl of 3 to 6 carbons, C₁₋₆ alkyl substituted cycloalkyl of 3 to6 carbons, alkenyl of 2 to 6 carbons and having 1 or 2 double bonds,alkynyl of 2 to 6 carbons, alkenyl-alkynyl of 4 to 6 carbons,alkynyl-alkenyl of 4 to 6 carbons, Cl, Br, I, or —COOR₁; Z is —C≡C—,—(CR₁═CR₁)_(n′) where n′ is an integer having the value 1-5, —CO—NR₁—,NR₁—CO—; —CO—O—, —O—CO—, —CS—NR₁—, NR₁—CS—, —CO—S—, —N═N—; —NR₁—CO—NR₁—;R₁ is independently H or alkyl of 1 to 6 carbons; R₂ is independently H,alkyl of 1 to 6 carbons, F, Cl, Br, I, CF₃, fluoro substituted alkyl of1 to 6 carbons, alkoxy of 1 to 6 carbons, or alkylthio of 1 to 6carbons; R₃ is independently alkyl of 1 to 6 carbons, F, Cl, Br, I,fluoro substituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6carbons, alkylthio of 1 to 6 carbons or benzyl; m is an integer havingthe values 0 to 3; n is an integer having the values of 0 or 1; p is aninteger having the values of 0 or 1; W is —C(R₅)₂— or —CR₅═CR₅—; R₅ isindependently H, halogen, or alkyl of 1 to 3 carbons with the provisothat when W is —C(R₅)₂— then at least one R₅ is alkyl of 1 to 3 carbons,and R₈ is H, alkyl of 1 to 6 carbons, —CH₂O(C₁₋₆-alkyl),CH₂OCO(C₁₋₆-alkyl) or a cation of a pharmaceutically acceptable base.28-32. (canceled)
 33. A compound of the formula

wherein A is a phenyl or naphthyl group, or heteroaryl selected from agroup consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl,pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyland heteroaryl groups being optionally substituted with one or two R₂groups; X is O, S, NR or CO where R is H or alkyl of 1 to 6 carbons; Yis H, alkyl of 1 to 10 carbons, benzyl, C₁₋₆ alkyl or halogensubstituted benzyl, fluoro-substituted alkyl of 1 to 10 carbons,cycloalkyl of 3 to 6 carbons, C₁₋₆ alkyl substituted cycloalkyl of 3 to6 carbons, alkenyl of 2 to 6 carbons and having 1 or 2 double bonds,alkynyl of 2 to 6 carbons, alkenyl-alkynyl of 4 to 6 carbons,alkynyl-alkenyl of 4 to 6 carbons, Cl, Br, I, OR₇, CH₂—NRR₇ or —COOR₁; Zis —C≡C—, —(CR₁═CR₁)_(n′) where n′ is an integer having the value 1-5,—CO—NR₁—, NR₁—CO—; —CO—O—, —O—CO—, —CS—NR₁—, NR₁—CS—, —CO—S—, —N═N—;—NR₁—CO—NR₁—; R₁ is independently H or alkyl of 1 to 6 carbons; R₂ isindependently H, alkyl of 1 to 6 carbons, F, Cl, Br, I, CF₃, fluorosubstituted alkyl of 1 to 6 carbons, alkoxy of 1 to 6 carbons, oralkylthio of 1 to 6 carbons; R₃ is independently alkyl of 1 to 6carbons, F, Cl, Br, I, fluoro substituted alkyl of 1 to 6 carbons, OH,SH, alkoxy of 1 to 6 carbons, alkylthio of 1 to 6 carbons or benzyl; mis an integer having the values 0 to 3; R₄ is independently H, alkyl of1 to 6 carbons, or F; fluorosubstituted alkyl of 1 to 6 carbons, orhalogen; o is an integer having the values of 0 to 4; W is —C(R₅)₂— or—CR₅═CR₅—; R₅ is independently H, halogen, or alkyl of 1 to 3 carbonswith the proviso that when W is —C(R₅)₂— then at least one R₅ is alkylof 1 to 3 carbons, and R₇ is H, alkyl of 1 to 6 carbons, cycloalkyl of 3to 6 carbons or C₁₋₆ alkyl substituted cycloalkyl of 1 to 6 carbons, andR₈ is H, alkyl of 1 to 6 carbons, —CH₂O(C₁₋₆-alkyl), CH₂OCO(C₁₋₆-alkyl)or a cation of a pharmaceutically acceptable base. 34-39. (canceled) 40.A compound of the formula

wherein A is a phenyl or naphthyl group, or heteroaryl selected from agroup consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl,pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyland heteroaryl groups being optionally substituted with one or two R₂groups; Y is alkenyl-alkynyl of 4 to 6 carbons, alkynyl-alkenyl of 4 to6 carbons, OR₇, CH₂—NRR₇ or —COOR₁; Z is —C≡C—, —CO—O—, —NR₁—CO—NR₁—; Ris independently H or alkyl of 1 to 6 carbons; R₁ is independently H oralkyl of 1 to 6 carbons; R₂ is independently H, alkyl of 1 to 6 carbons,F, Cl, Br, I, CF₃, fluoro substituted alkyl of 1 to 6 carbons, alkoxy of1 to 6 carbons, or alkylthio of 1 to 6 carbons; R₃ is independentlyalkyl of 1 to 6 carbons, F, Cl, Br, I, fluoro substituted alkyl of 1 to6 carbons, OH, SH, alkoxy of 1 to 6 carbons, alkylthio of 1 to 6 carbonsor benzyl; m is an integer having the values 0 to 3; R₄ is independentlyH, alkyl of 1 to 6 carbons, or F; fluorosubstituted alkyl of 1 to 6carbons, or halogen; o is an integer having the values of 0 to 4; R₇ isH, alkyl of 1 to 6 carbons, cycloalkyl of 3 to 6 carbons or C₁₋₆ alkylsubstituted cycloalkyl of 1 to 6 carbons, and R₈ is H, alkyl of 1 to 6carbons, —CH₂O(C₁₋₆-alkyl), CH₂OCO(C₁₋₆-alkyl) or a cation of apharmaceutically acceptable base. 41-43. (canceled)
 44. A compound ofthe formula

wherein A is a phenyl or naphthyl group, or heteroaryl selected from agroup consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl,pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyland heteroaryl groups being optionally substituted with one or two R₂groups; Y is alkenyl of 2 to 6 carbons, alkynyl of 2 to 6 carbons,alkenyl-alkynyl of 4 to 6 carbons, alkynyl-alkenyl of 4 to 6 carbons; Zis —C≡C—, —CO—O—, —NR₁—CO—NR₁—; R₁ is independently H or alkyl of 1 to 6carbons; R₂ is independently H, alkyl of 1 to 6 carbons, F, Cl, Br, I,CF₃, fluoro substituted alkyl of 1 to 6 carbons, alkoxy of 1 to 6carbons, or alkylthio of 1 to 6 carbons; R₃ is independently alkyl of 1to 6 carbons, F, Cl, Br, I, fluoro substituted alkyl of 1 to 6 carbons,OH, SH, alkoxy of 1 to 6 carbons, alkylthio of 1 to 6 carbons or benzyl;m is an integer having the values 0 to 3; R₇ is H, alkyl of 1 to 6carbons, cycloalkyl of 3 to 6 carbons or C₁₋₆ alkyl substitutedcycloalkyl of 1 to 6 carbons, and R₈ is H, alkyl of 1 to 6 carbons,—CH₂O(C₁₋₆-alkyl), CH₂OCO(C₁₋₆-alkyl) or a cation of a pharmaceuticallyacceptable base. 45-47. (canceled)
 48. A compound of the formula

wherein A is a phenyl or naphthyl group, or heteroaryl selected from agroup consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl,pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyland heteroaryl groups being optionally substituted with one or two R₂groups; Z is —C≡C—, —CO—O—, —NR₁—CO—NR₁—; R is H or alkyl of 1 to 6carbons; R₁ is independently H or alkyl of 1 to 6 carbons; R₂ isindependently H, alkyl of 1 to 6 carbons, F, Cl, Br, I, CF₃, fluorosubstituted alkyl of 1 to 6 carbons, alkoxy of 1 to 6 carbons, oralkylthio of 1 to 6 carbons; R₃ is independently alkyl of 1 to 6carbons, F, Cl, Br, I, fluoro substituted alkyl of 1 to 6 carbons, OH,SH, alkoxy of 1 to 6 carbons, alkylthio of 1 to 6 carbons or benzyl; mis an integer having the values 0 to 3; R₇ is H, alkyl of 1 to 6carbons, cycloalkyl of 3 to 6 carbons or C₁₋₆ alkyl substitutedcycloalkyl of 1 to 6 carbons, and R₈ independently is H, alkyl of 1 to 6carbons, —CH₂O(C₁₋₆-alkyl), CH₂OCO(C₁₋₆-alkyl) or a cation of apharmaceutically acceptable base. 49-51. (canceled)
 52. A compound ofthe formula

wherein the dashed line represents a bond or absence of a bond; A is aphenyl or naphthyl group, or heteroaryl selected from a group consistingof pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl,thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyl andheteroaryl groups being optionally substituted with one or two R₂groups; X is NRR₇, or COOR₈; Y is H, alkenyl of 2 to 6 carbons,alkenyl-alkynyl of 4 to 6 carbons, alkynyl-alkenyl of 4 to 6 carbons,OR₇ or —COOR₁; Z is —C≡C—, —CO—O—, —NR₁—CO—NR₁—; R is independently H oralkyl of 1 to 6 carbons; R₁ is independently H or alkyl of 1 to 6carbons; R₂ is independently H, alkyl of 1 to 6 carbons, F, Cl, Br, I,CF₃, fluoro substituted alkyl of 1 to 6 carbons, alkoxy of 1 to 6carbons, or alkylthio of 1 to 6 carbons; R₃ is independently alkyl of 1to 6 carbons, F, Cl, Br, I, fluoro substituted alkyl of 1 to 6 carbons,OH, SH, alkoxy of 1 to 6 carbons, alkylthio of 1 to 6 carbons or benzyl;m is an integer having the values 0 to 3; R₄ is independently H, alkylof 1 to 6 carbons, or F; fluorosubstituted alkyl of 1 to 6 carbons, orhalogen; o is an integer having the values of 0 to 4; R₇ is H, alkyl of1 to 6 carbons, cycloalkyl of 3 to 6 carbons or C₁₋₆ alkyl substitutedcycloalkyl of 1 to 6 carbons, and R₈ independently is H, alkyl of 1 to 6carbons, —CH₂O(C₁₋₆-alkyl), CH₂OCO(C₁₋₆-alkyl) or a cation of apharmaceutically acceptable base. 53-55. (canceled)
 56. A compound ofthe formula

wherein A is a phenyl or naphthyl group, or heteroaryl selected from agroup consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl,pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyland heteroaryl groups being optionally substituted with one or two R₂groups; Y is, alkenyl of 2 to 6 carbons, alkenyl-alkynyl of 4 to 6carbons, or alkynyl-alkenyl of 4 to 6 carbons; Z is —C≡C—, —CO—O—,—NR₁—CO—NR₁—; R₁ is independently H or alkyl of 1 to 6 carbons; R₂ isindependently H, alkyl of 1 to 6 carbons, F, Cl, Br, I, CF₃, fluorosubstituted alkyl of 1 to 6 carbons, alkoxy of 1 to 6 carbons, oralkylthio of 1 to 6 carbons; R₃ is independently alkyl of 1 to 6carbons, F, Cl, Br, I, fluoro substituted alkyl of 1 to 6 carbons, OH,SH, alkoxy of 1 to 6 carbons, alkylthio of 1 to 6 carbons or benzyl; mis an integer having the values 0 to 3; R₄ is independently H, alkyl of1 to 6 carbons, or F; fluorosubstituted alkyl of 1 to 6 carbons, orhalogen; o is an integer having the values of 0 to 4, and R₈ is H, alkylof 1 to 6 carbons, —CH₂O(C₁₋₆-alkyl), CH₂OCO(C₁₋₆-alkyl) or a cation ofa pharmaceutically acceptable base. 57-59. (canceled)
 60. A compound ofthe formula

wherein A is a phenyl or naphthyl group, or heteroaryl selected from agroup consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl,pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyland heteroaryl groups being optionally substituted with one or two R₂groups; Z is —C≡C—, —CO—O—, —NR₁—CO—NR₁—; R₁ is independently H or alkylof 1 to 6 carbons; R₂ is independently H, alkyl of 1 to 6 carbons, F,Cl, Br, I, CF₃, fluoro substituted alkyl of 1 to 6 carbons, alkoxy of 1to 6 carbons, or alkylthio of 1 to 6 carbons; R₃ is independently alkylof 1 to 6 carbons, F, Cl, Br, I, fluoro substituted alkyl of 1 to 6carbons, OH, SH, alkoxy of 1 to 6 carbons, alkylthio of 1 to 6 carbonsor benzyl; m is an integer having the values 0 to 3, and R₈independently is H, alkyl of 1 to 6 carbons, —CH₂O(C₁₋₆-alkyl),CH₂OCO(C₁₋₆-alkyl) or a cation of a pharmaceutically acceptable base.61-63. (canceled)
 64. A compound of the formula

wherein A is a phenyl or naphthyl group, or heteroaryl selected from agroup consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl,pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyland heteroaryl groups being optionally substituted with one or two R₂groups; Z is —C≡C—, —CO—O—, —NR₁—CO—NR₁—; R₁ is independently H or alkylof 1 to 6 carbons; R₂ is independently H, alkyl of 1 to 6 carbons, F,Cl, Br, I, CF₃, fluoro substituted alkyl of 1 to 6 carbons, alkoxy of 1to 6 carbons, or alkylthio of 1 to 6 carbons; R₃ is independently alkylof 1 to 6 carbons, F, Cl, Br, I, fluoro substituted alkyl of 1 to 6carbons, OH, SH, alkoxy of 1 to 6 carbons, alkylthio of 1 to 6 carbonsor benzyl; m is an integer having the values 0 to 3, and R₈independently is H, alkyl of 1 to 6 carbons, —CH₂O(C₁₋₆-alkyl),CH₂OCO(C₁₋₆-alkyl) or a cation of a pharmaceutically acceptable base.65-67. (canceled)
 68. A compound of the formula

wherein A is a phenyl or naphthyl group, or heteroaryl selected from agroup consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl,pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyland heteroaryl groups being optionally substituted with one or two R₂groups; Y is H, alkyl of 1 to 10 carbons, benzyl, C₁₋₆ alkyl or halogensubstituted benzyl, fluoro-substituted alkyl of 1 to 10 carbons,cycloalkyl of 3 to 6 carbons, C₁₋₆ alkyl substituted cycloalkyl of 3 to6 carbons, alkenyl of 2 to 6 carbons and having 1 or 2 double bonds,alkynyl of 2 to 6 carbons, alkenyl-alkynyl of 4 to 6 carbons,alkynyl-alkenyl of 4 to 6 carbons, Cl, Br, I, OR₇, CH₂—NRR₇ or —COOR₁; Ris independently H or alkyl of 1 to 6 carbons; R₁ is independently H oralkyl of 1 to 6 carbons; R₂ is independently H, alkyl of 1 to 6 carbons,F, Cl, Br, I, CF₃, fluoro substituted alkyl of 1 to 6 carbons, alkoxy of1 to 6 carbons, or alkylthio of 1 to 6 carbons; R₃ is independentlyalkyl of 1 to 6 carbons, F, Cl, Br, I, fluoro substituted alkyl of 1 to6 carbons, OH, SH, alkoxy of 1 to 6 carbons, alkylthio of 1 to 6 carbonsor benzyl; m is an integer having the values 0 to 3; R₄ is independentlyH, alkyl of 1 to 6 carbons, or F; fluorosubstituted alkyl of 1 to 6carbons, or halogen; o is an integer having the values of 0 to 4; R₇ isH, alkyl of 1 to 6 carbons, cycloalkyl of 3 to 6 carbons or C₁₋₆ alkylsubstituted cycloalkyl of 1 to 6 carbons, and R₈ is H, alkyl of 1 to 6carbons, —CH₂O(C₁₋₆-alkyl), CH₂OCO(C₁₋₆-alkyl) or a cation of apharmaceutically acceptable base. 69-71. (canceled)
 72. A compound ofthe formula

wherein A is a phenyl or naphthyl group, or heteroaryl selected from agroup consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl,pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyland heteroaryl groups being optionally substituted with one or two R₂groups; X is O or S; Y is H, alkyl of 1 to 10 carbons, benzyl, C₁₋₆alkyl or halogen substituted benzyl, fluoro-substituted alkyl of 1 to 10carbons, cycloalkyl of 3 to 6 carbons, C₁₋₆ alkyl substituted cycloalkylof 3 to 6 carbons, alkenyl of 2 to 6 carbons and having 1 or 2 doublebonds, alkynyl of 2 to 6 carbons, alkenyl-alkynyl of 4 to 6 carbons,alkynyl-alkenyl of 4 to 6 carbons, Cl, Br, I, OR₇, CH₂—NRR₇ or —COOR₁;R₁ is independently H or alkyl of 1 to 6 carbons; p is an integer havingthe values of 0 to 4; R₂ is independently H, alkyl of 1 to 6 carbons, F,Cl, Br, I, CF₃, fluoro substituted alkyl of 1 to 6 carbons, alkoxy of 1to 6 carbons, or alkylthio of 1 to 6 carbons; R₃ is independently alkylof 1 to 6 carbons, F, Cl, Br, I, fluoro substituted alkyl of 1 to 6carbons, OH, SH, alkoxy of 1 to 6 carbons, alkylthio of 1 to 6 carbonsor benzyl; m is an integer having the values 0 to 3; R₄ is independentlyH, alkyl of 1 to 6 carbons, or F; fluorosubstituted alkyl of 1 to 6carbons, or halogen; o is an integer having the values of 0 to 4; R₇ isH, alkyl of 1 to 6 carbons, cycloalkyl of 3 to 6 carbons or C₁₋₆ alkylsubstituted cycloalkyl of 1 to 6 carbons, and R₈ is H, alkyl of 1 to 6carbons, —CH₂O(C₁₋₆-alkyl), CH₂OCO(C₁₋₆-alkyl) or a cation of apharmaceutically acceptable base.
 73. A compound in accordance withclaim 72 where A is selected from the group consisting of phenyl,naphthyl, pyridyl, thienyl and furyl.
 74. A compound in accordance withclaim 73 where A is phenyl.
 75. A compound in accordance with claim 74where X is O, Y is cyclopropyl and R₈ is H, lower alkyl of 1 to 3carbons, —CH₂O(C₁₋₃-alkyl) or —CH₂OCO(C₁₋₃-alkyl) or a cation of apharmaceutically acceptable base.
 76. A compound of the formula

wherein A is a phenyl or naphthyl group, or heteroaryl selected from agroup consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl,pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyland heteroaryl groups being optionally substituted with one or two R₂groups; R₂ is independently H, alkyl of 1 to 6 carbons, F, Cl, Br, I,CF₃, fluoro substituted alkyl of 1 to 6 carbons, alkoxy of 1 to 6carbons, or alkylthio of 1 to 6 carbons; R₃ is independently alkyl of 1to 6 carbons, F, Cl, Br, I, fluoro substituted alkyl of 1 to 6 carbons,OH, SH, alkoxy of 1 to 6 carbons, alkylthio of 1 to 6 carbons or benzyl;m is an integer having the values 0 to 3, and R₈ independently is H,alkyl of 1 to 6 carbons, —CH₂O(C₁₋₆-alkyl), CH₂OCO(C₁₋₆-alkyl) or acation of a pharmaceutically acceptable base. 77-79. (canceled)
 80. Acompound of the formula

wherein A is a phenyl or naphthyl group, or heteroaryl selected from agroup consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl,pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyland heteroaryl groups being optionally substituted with one or two R₂groups; X is O or S; Y is H, alkyl of 1 to 10 carbons, benzyl, C₁₋₆alkyl or halogen substituted benzyl, fluoro-substituted alkyl of 1 to 10carbons, cycloalkyl of 3 to 6 carbons, C₁₋₆ alkyl substituted cycloalkylof 3 to 6 carbons, alkenyl of 2 to 6 carbons and having 1 or 2 doublebonds, alkynyl of 2 to 6 carbons, alkenyl-alkynyl of 4 to 6 carbons,alkynyl-alkenyl of 4 to 6 carbons, Cl, Br, I, OR₇, CH₂—NRR₇ or —COOR₁;R₁ is independently H or alkyl of 1 to 6 carbons; R₂ is independently H,alkyl of 1 to 6 carbons, F, Cl, Br, I, CF₃, fluoro substituted alkyl of1 to 6 carbons, alkoxy of 1 to 6 carbons, or alkylthio of 1 to 6carbons; R₃ is independently alkyl of 1 to 6 carbons, F, Cl, Br, I,fluoro substituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6carbons, alkylthio of 1 to 6 carbons or benzyl; m is an integer havingthe values 0 to 3; R₄ is independently H, alkyl of 1 to 6 carbons, or F;fluorosubstituted alkyl of 1 to 6 carbons, or halogen; o is an integerhaving the values of 0 to 4; R₇ is H, alkyl of 1 to 6 carbons,cycloalkyl of 3 to 6 carbons or C₁₋₆ alkyl substituted cycloalkyl of 1to 6 carbons, and R₈ is H, alkyl of 1 to 6 carbons, —CH₂O(C₁₋₆-alkyl),CH₂OCO(C₁₋₆-alkyl) or a cation of a pharmaceutically acceptable base.81. A compound in accordance with claim 80 where A is selected from thegroup consisting of phenyl, naphthyl, pyridyl, thienyl and furyl.
 82. Acompound in accordance with claim 81 where A is phenyl.
 83. A compoundin accordance with claim 82 where X is O, Y is CH≡C—, R₈ is H, loweralkyl of 1 to 3 carbons, —CH₂O(C₁₋₃-alkyl) or —CH₂OCO(C₁₋₃-alkyl) or acation of a pharmaceutically acceptable base.